Sulfoximine substituted quinazolines for pharmaceutical compositions

ABSTRACT

This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I 
                         
wherein Ar, R 1  and R 2  are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Aug. 21, 2015, isnamed 01-2934-US-2_SL.txt and is 942 bytes in size.

FIELD OF THE INVENTION

This invention relates to sulfoximine substituted quinazolinederivatives and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a orMNK2b) kinase inhibitors, pharmaceutical compositions containing themand their use in the treatment or amelioration of MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a or MNK2b) mediated disorders.

Moreover, the present invention relates to the use of sulfoximinesubstituted quinazoline derivatives of the invention for the productionof pharmaceutical compositions for the prophylaxis and/or treatment ofdiseases which can be influenced by the inhibition of the kinaseactivity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) orfurther variants thereof. Particularly, the present invention relates tothe use of sulfoximine substituted quinazoline derivatives of theinvention for the production of pharmaceutical compositions for theprophylaxis and/or therapy of metabolic diseases, such as diabetes,hyperlipidemia and obesity, hematopoietic disorders, neurodegenerativediseases, kidney damage, inflammatory disorders, and cancer and theirconsecutive complications and disorders associated therewith.

BACKGROUND OF THE INVENTION

Metabolic diseases are diseases caused by an abnormal metabolic processand may either be congenital due to an inherited enzyme abnormality oracquired due to a disease of an endocrine organ or failure of ametabolically important organ such as the liver or the pancreas.

The present invention is more particularly directed to the treatmentand/or prophylaxis of in particular metabolic diseases of the lipid andcarbohydrate metabolism and the consecutive complications and disordersassociated therewith.

Lipid disorders cover a group of conditions which cause abnormalities inthe level and metabolism of plasma lipids and lipoproteins. Thus,hyperlipidemias are of particular clinical relevance since theyconstitute an important risk factor for the development ofatherosclerosis and subsequent vascular diseases such as coronary heartdisease.

Diabetes mellitus is defined as a chronic hyperglycemia associated withresulting damages to organs and dysfunctions of metabolic processes.Depending on its etiology, one differentiates between several forms ofdiabetes, which are either due to an absolute (lacking or decreasedinsulin secretion) or to a relative lack of insulin. Diabetes mellitusType I (IDDM, insulin-dependent diabetes mellitus) generally occurs inadolescents under 20 years of age. It is assumed to be of auto-immuneetiology, leading to an insulitis with the subsequent destruction of thebeta cells of the islets of Langerhans which are responsible for theinsulin synthesis. In addition, in latent autoimmune diabetes in adults(LADA; Diabetes Care. 8: 1460-1467, 2001) beta cells are being destroyeddue to autoimmune attack. The amount of insulin produced by theremaining pancreatic islet cells is too low, resulting in elevated bloodglucose levels (hyperglycemia). Diabetes mellitus Type II generallyoccurs at an older age. It is above all associated with a resistance toinsulin in the liver and the skeletal muscles, but also with a defect ofthe islets of Langerhans. High blood glucose levels (and also high bloodlipid levels) in turn lead to an impairment of beta cell function and toan increase in beta cell apoptosis.

Diabetes is a very disabling disease, because today's commonanti-diabetic drugs do not control blood sugar levels well enough tocompletely prevent the occurrence of high and low blood sugar levels.Out of range blood sugar levels are toxic and cause long-termcomplications for example retinopathy, renopathy, neuropathy andperipheral vascular disease. There is also a host of related conditions,such as obesity, hypertension, heart disease and hyperlipidemia, forwhich persons with diabetes are substantially at risk.

Obesity is associated with an increased risk of follow-up diseases suchas cardiovascular diseases, hypertension, diabetes, hyperlipidemia andan increased mortality. Diabetes (insulin resistance) and obesity arepart of the “metabolic syndrome” which is defined as the linkage betweenseveral diseases (also referred to as syndrome X, insulin-resistancesyndrome, or deadly quartet). These often occur in the same patients andare major risk factors for development of diabetes type II andcardiovascular disease. It has been suggested that the control of lipidlevels and glucose levels is required to treat diabetes type II, heartdisease, and other occurrences of metabolic syndrome (see e.g., Diabetes48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002).

In one embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of metabolic diseases of the carbohydrate metabolismand their consecutive complications and disorders such as impairedglucose tolerance, diabetes (preferably diabetes type II), diabeticcomplications such as diabetic gangrene, diabetic arthropathy, diabeticosteopenia, diabetic glomerosclerosis, diabetic nephropathy, diabeticdermopathy, diabetic neuropathy, diabetic cataract and diabeticretinopathy, diabetic maculopathy, diabetic feet syndrome, diabetic comawith or without ketoacidosis, diabetic hyperosmolar coma, hypoglycemiccoma, hyperglycemic coma, diabetic acidosis, diabetic ketoacidosis,intracapillary glomerulonephrosis, Kimmelstiel-Wilson syndrome, diabeticamyotrophy, diabetic autonomic neuropathy, diabetic mononeuropathy,diabetic polyneuropathy, diabetic angiopathies, diabetic peripheralangiopathy, diabetic ulcer, diabetic arthropathy, or obesity indiabetes.

In a further embodiment the compounds and compositions of the presentinvention are useful for the treatment and/or prophylaxis of metabolicdiseases of the lipid metabolism (i.e. lipid disorders) and theirconsecutive complications and disorders such as hypercholesterolemia,familial hypercholesterolemia, Fredrickson's hyperlipoproteinemia,hyperbetalipoproteinemia, hyperlipidemia, low-density-lipoprotein-type[LDL] hyperlipoproteinemia, pure hyperglyceridemia, endogenoushyperglyceridemia, isolated hypercholesterolemia, isolatedhypertroglyceridemia, cardiovascular diseases such as hypertension,ischemia, varicose veins, retinal vein occlusion, atherosclerosis,angina pectoris, myocardial infarction, stenocardia, pulmonaryhypertension, congestive heart failure, glomerulopaty, tubulointestitialdisorders, renal failure, angiostenosis, or cerebrovascular disorders,such as cerebral apoplexy.

In a further embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of hematopoetic disorders and their consecutivecomplications and disorders such as acute myeloid leukemia (AML), MorbusHodgkin, Non-Hodgkin's lymphoma; hematopoetic disease, acutenon-lymphocytic leukemia (ANLL), myeloproliferative disease acutepromyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL),multiple myeloma, polycythemia vera, lymphoma, acute lymphocyticleukemia (ALL), chronic lymphocytic leukemia (CCL), Wilm's tumor, orEwing's Sarcoma.

In a further embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of cancer and consecutive complications and disorderssuch as cancer of the upper gastrointestinal tract, pancreaticcarcinoma, breast cancer, colon cancer, ovarian carcinoma, cervixcarcinoma, endometrial cancer, brain tumor, testicular cancer, laryngealcarcinoma, osteocarcinoma, prostatic cancer, retinoblastoma, livercarcinoma, lung cancer, neuroblastoma, renal carcinoma, thyroidcarcinoma, esophageal cancer, soft tissue sarcoma, skin cancer,osteosarcoma, rhabdomyosarcoma, bladder cancer, metastatic cancer,cachexia, or pain.

Certain anti-cancer drugs such as cisplatin are linked to serious sideeffects such as nephrotoxicity or ototoxicity, which can be doselimiting. Activation of MNKs has been linked to these side effects. In afurther embodiment of the present invention, the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of ear or kidney damage, in particular for theprevention or treatment of ear and kidney drug induced damage.

Furthermore, the present invention relates to the use of the compoundsaccording to the invention for the production of pharmaceuticalcompositions for the prophylaxis and/or therapy of cytokine relateddiseases.

Such diseases include inflammatory diseases, autoimmune diseases,destructive bone disorders, proliferative disorders, infectiousdiseases, neurodegenerative diseases, allergies, or other conditionsassociated with proinflammatory cytokines. Allergic and inflammatorydiseases such as acute or chronic inflammation, chronic inflammatoryarthritis, rheumatoid arthritis, psoriasis, COPD, inflammatory boweldisease, asthma and septic shock and their consecutive complications anddisorders associated therewith.

Inflammatory diseases like rheumatoid arthritis, inflammatory lungdiseases like COPD, inflammatory bowel disease and psoriasis afflict onein three people in the course of their lives. Not only do those diseasesimpose immense health care costs, but also they are often crippling anddebilitating.

Although inflammation is the unifying pathogenic process of theseinflammatory diseases below, the current treatment approach is complexand is generally specific for any one disease. Many of the currenttherapies available today only treat the symptoms of the disease and notthe underlying cause of inflammation.

The compositions of the present invention are useful for the treatmentand/or prophylaxis of inflammatory diseases and consecutivecomplications and disorders. such as chronic or acute inflammation,inflammation of the joints such as chronic inflammatory arthritis,rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenilerheumatoid arthritis, Reiter's syndrome, rheumatoid traumatic arthritis,rubella arthritis, acute synovitis and gouty arthritis; inflammatoryskin diseases such as sunburn, psoriasis, erythrodermic psoriasis,pustular psoriasis, eczema, dermatitis, acute or chronic graftformation, atopic dermatitis, contact dermatitis, urticaria andscleroderma; inflammation of the gastrointestinal tract such asinflammatory bowel disease, Crohn's disease and related conditions,ulcerative colitis, colitis, and diverticulitis; nephritis, urethritis,salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupuserythematosus and related disorders, multiple sclerosis, asthma,meningitis, myelitis, encephalomyelitis, encephalitis, phlebitis,thrombophlebitis, respiratory diseases such as asthma, bronchitis,chronic obstructive pulmonary disease (COPD), inflammatory lung diseaseand adult respiratory distress syndrome, and allergic rhinitis;endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis,rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valvedisease, rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjogren's syndrome, neuroinflammatory disease, sepsis, conjunctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis.oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, goodpasture's disease, crescenticglomerulonephritis, pancreatitis, endomyometritis, myometritis,metritis, cervicitis, endocervicitis, exocervicitis, parametritis,tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

Moreover, cytokines are also believed to be implicated in the productionand development of various cardiovascular and cerebrovascular disorderssuch as congestive heart disease, myocardial infarction, the formationof atherosclerotic plaques, hypertension, platelet aggregation, angina,stroke, Alzheimer's disease, reperfusion injury, vascular injuryincluding restenosis and peripheral vascular disease, and, for example,various disorders of bone metabolism such as osteoporosis (includingsenile and postmenopausal osteoporosis), Paget's disease, bonemetastases, hypercalcaemia, hyperparathyroidism, osteosclerosis,osteoporosis and periodontitis, and the abnormal changes in bonemetabolism which may accompany rheumatoid arthritis and osteoarthritis.

Excessive cytokine production has also been implicated in mediatingcertain complications of bacterial, fungal and/or viral infections suchas endotoxic shock, septic shock and toxic shock syndrome and inmediating certain complications of CNS surgery or injury such asneurotrauma and ischaemic stroke.

Excessive cytokine production has, moreover, been implicated inmediating or exacerbating the development of diseases involvingcartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renalfibrosis, the cachexia found in certain chronic diseases such asmalignant disease and acquired immune deficiency syndrome (AIDS), tumourinvasiveness and tumour metastasis and multiple sclerosis. The treatmentand/or prophylaxis of these diseases are also contemplated by thepresent invention

Additionally, the inventive compositions may be used to treatinflammation associated with autoimmune diseases including, but notlimited to, systemic lupus erythematosis, Addison's disease, autoimmunepolyglandular disease (also known as autoimmune polyglandular syndrome),glomerulonephritis, rheumatoid arthritis scleroderma, chronicthyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmunehemolytic anemia, glomerulonephritis, rheumatoid arthritis autoimmuneneutropenia, thrombocytopenia, atopic dermatitis, chronic activehepatitis, myasthenia gravis, multiple sclerosis, inflammatory boweldisease, ulcerative colitis, Crohn's disease, psoriasis, and graft vs.host disease.

In a further embodiment the compositions of the present invention may beused for the treatment and prevention of infectious diseases such assepsis, septic shock, Shigellosis, and Helicobacter pylori and viraldiseases including herpes simplex type 1 (HSV-1), herpes simplex type 2(HSV-2), cytomegalovirus, Epstein-Barr, human immunodeficiency virus(HIV), acute hepatitis infection (including hepatitis A, hepatits B, andhepatitis C), HIV infection and CMV retinitis, AIDS or malignancy,malaria, mycobacterial infection and meningitis. These also includeviral infections, by influenza virus, varicella-zoster virus (VZV),Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7(HHV-7), human herpesvirus-8 (HHV-8), Poxvirus, Vacciniavirus,Monkeypoxvirus, pseudorabies and rhinotracheitis.

The compositions of the present invention may also be used topically inthe treatment or prophylaxis of topical disease states mediated by orexacerbated by excessive cytokine production, such as inflamed joints,eczema, psoriasis and other inflammatory skin conditions such assunburn; inflammatory eye conditions including conjunctivitis; pyresis,pain and other conditions associated with inflammation.

Periodontal disease has also been implemented in cytokine production,both topically and systemically. Hence, use of compositions of thepresent invention to control the inflammation associated with cytokineproduction in such peroral diseases such as gingivitis and periodontitisis another aspect of the present invention.

Finally, the compositions of the present invention may also be used totreat or prevent neurodegenerative disease selected from Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, frontotemporal lobar dementia, spinocerebellarataxia, dementia with Lewy bodies, cerebral ischemia orneurodegenerative disease caused by traumatic injury, glutamateneurotoxicity or hypoxia.

In a preferred embodiment the compositions of the present invention maybe used to treat or prevent a disease selected from chronic or acuteinflammation, chronic inflammatory arthritis, rheumatoid arthritis,psoriasis, COPD, inflammatory bowel disease, septic shock, Crohn'sdisease, ulcerative colitis, multiple sclerosis and asthma.

Protein kinases are important enzymes involved in the regulation of manycellular functions. The LK6-serine/threonine-kinase gene of Drosophilamelanogaster was described as a short-lived kinase which can associatewith microtubules (J. Cell Sci. 1997, 110(2): 209-219). Genetic analysisin the development of the compound eye of Drosophila suggested a role inthe modulation of the RAS signal pathway (Genetics 2000 156(3):1219-1230). The closest human homologues of Drosophila LK6-kinase arethe MAP-kinase interacting kinase 2 (MNK2, e.g. the variants MNK2a andMNK2b) and MAP-kinase interacting kinase 1 (MNK1) and variants thereof.These kinases are mostly localized in the cytoplasm. MNKs arephosphorylated by the p42 MAP kinases Erk1 and Erk2 and the p38-MAPkinases. This phosphorylation is triggered in a response to growthfactors, phorbol esters and oncogenes such as Ras and Mos, and by stresssignaling molecules and cytokines. The phosphorylation of MNK proteinsstimulates their kinase activity towards eukaryotic initiation factor 4E(eIF4E) (EMBO J. 16: 1909-1920, 1997; Mol Cell Biol 19, 1871-1880, 1990;Mol Cell Biol 21, 743-754, 2001). Simultaneous disruption of both, theMNK1 and MNK2 gene in mice diminishes basal and stimulated eIF4Ephosphorylation (Mol Cell Biol 24, 6539-6549, 2004). Phosphorylation ofeIF4E results in a regulation of the protein translation (Mol Cell Biol22: 5500-5511, 2001).

There are different hypotheses describing the mode of the stimulation ofthe protein translation by MNK proteins. Most publications describe apositive stimulatory effect on the cap-dependent protein translationupon activation of MAP kinase-interacting kinases. Thus, the activationof MNK proteins can lead to an indirect stimulation or regulation of theprotein translation, e.g. by the effect on the cytosolic phospholipase 2alpha (BBA 1488:124-138, 2000).

WO 03/037362 discloses a link between human MNK genes, particularly thevariants of the human MNK2 genes, and diseases which are associated withthe regulation of body weight or thermogenesis. It is postulated thathuman MNK genes, particularly the MNK2 variants are involved in diseasessuch as e.g. metabolic diseases including obesity, eating disorders,cachexia, diabetes mellitus, hypertension, coronary heart disease,hypercholesterolemia, dyslipidemia, osteoarthritis, biliary stones,cancer of the genitals and sleep apnea, and in diseases connected withthe ROS defense, such as e.g. diabetes mellitus and cancer. WO 03/03762moreover discloses the use of nucleic acid sequences of the MAPkinase-interacting kinase (MNK) gene family and amino acid sequencesencoding these and the use of these sequences or of effectors of MNKnucleic acids or polypeptides, particularly MNK inhibitors andactivators in the diagnosis, prophylaxis or therapy of diseasesassociated with the regulation of body weight or thermogenesis.

WO 02/103361 describes the use of kinases 2a and 2b (MNK2a and MNK2b)interacting with the human MAP kinase in assays for the identificationof pharmacologically active ingredients, particularly useful for thetreatment of diabetes mellitus type 2. Moreover, WO 02/103361 disclosesalso the prophylaxis and/or therapy of diseases associated with insulinresistance, by modulation of the expression or the activity of MNK2a orMNK2b. Apart from peptides, peptidomimetics, amino acids, amino acidanalogues, polynucleotides, polynucleotide analogues, nucleotides andnucleotide analogues, 4-hydroxybenzoic acid methyl ester are describedas a substance which binds the human MNK2 protein.

First evidence for a role of MNKs in inflammation was provided bystudies demonstrating activation of MNK1 by proinflammatory stimuli. Thecytokines TNFα and IL-1β trigger the activation of MNK1 in vitro(Fukunaga and Hunter, EMBO J 16(8): 1921-1933, 1997) and induce thephosphorylation of the MNK-specific substrate eIF4E in vivo (Ueda etal., Mol Cell Biol 24(15): 6539-6549, 2004). In addition, administrationof lipopolysaccharide (LPS), a potent stimulant of the inflammatoryresponse, induces activation of MNK1 and MNK2 in mice, concomitant witha phosphorylation of their substrate eIF4E (Ueda et al., Mol Cell Biol24(15): 6539-6549, 2004).

Furthermore, MNK1 has been shown to be involved in regulating theproduction of proinflammatory cytokines. MNK1 enhances expression of thechemokine RANTES (Nikolcheva et al., J Clin Invest 110, 119-126, 2002).RANTES is a potent chemo-tractant of monocytes, eosinophils, basophilesand, natural killer cells. It activates and induces proliferation of Tlymphocytes, mediates degranulation of basophils and induces therespiratory burst in eosinophils (Conti and DiGioacchino, Allergy AsthmaProc 22(3):133-7, 2001).

WO 2005/00385 and Buxade et al., Immunity 23: 177-189, August 2005 bothdisclose a link between MNKs and the control of TNFα biosynthesis. Theproposed mechanism is mediated by a regulatory AU-rich element (ARE) inthe TNFα mRNA. Buxade et al. demonstrate proteins binding andcontrolling ARE function to be phosphorylated by MNK1 and MNK2.Specifically MNK-mediated phosphorylation of the ARE-binding proteinhnRNP A1 has been suggested to enhance translation of the TNFα mRNA.

TNFα is not the only cytokine regulated by an ARE. Functional AREs arealso found in the transcripts of several interleukins, interferones andchemokines (Khabar, J lnterf Cytokine Res 25: 1-10, 2005). TheMNK-mediated phosphorylation of ARE-binding proteins has thus thepotential to control biosynthesis of cytokines in addition to that ofTNFα.

Current evidence demonstrates MNKs as down stream targets ofinflammatory signalling as well as mediators of the inflammatoryresponse. Their involvement in the production of TNFα, RANTES, andpotentially additional cytokines suggests inhibition of MNKs as strategyfor anti-inflammatory therapeutic intervention.

MNK1 and MNK2 (including all splice forms) phosphorylate the translationfactor eIF4E on Serine 209. MNK1/2 double knockout mice completely lackphosphorylation on Serine 209, indicating that MNK kinase are the onlykinases able to phosphorylate this site in vivo (Ueda et al., Mol CellBiol. 2004; 24(15):6539-49). eIF4E is overexpressed in a wide range ofhuman malignancies, and high eIF4E expression is frequently associatedwith more aggressive disease and poor prognosis. Furthermore, eIF4E canact as an oncogene when assayed in standard assays for oncogenicactivity (e.g. Ruggero et al., Nat Med. 2004 May; 10(5):484-6). eIF4Eexcerts its oncogenic activity by stimulating the translation ofoncogenes such as c-myc and cyclinD1 (Culjkovic et al., J Cell Biol.2006; 175(3):415-26), by increasing the expression of pro-survivalfactors such as MCP-1 (Wendel et al., Genes Dev. 2007; 21(24):3232-7)and by positively regulating pathways of drug resistance (Wendel et al.,Nature 2004; 428(6980):332-7; Graff et el., Cancer Res. 2008;68(3):631-4; De Benedetti and Graff, Oncogene 2004; 23(18):3189-99;Barnhart and Simon, J Clin Invest. 2007; 117(9):2385-8). Suppression ofeIF4E expression by antisense oligonucleotides has shown promise inpreclinical experiments with human tumor cells (Graff et al., J ClinInvest. 2007; 117(9):2638-48). It has been shown that phosphorylation onSer209 is strictly required for the oncogenic activity of eIF4E in vitroand in vivo (Topisirovic et al., Cancer Res. 2004; 64(23):8639-42;Wendel et al., Genes Dev. 2007; 21(24):3232-7). Thus, inhibition of MNK1and MNK2 is expected to have beneficial effects in human malignancies.

Inhibitors of MNK (referred to as CGP57380 and CGP052088) have beendescribed (cf. Mol. Cell. Biol. 21, 5500, 2001; Mol Cell Biol Res Comm3, 205, 2000; Genomics 69, 63, 2000). CGP052088 is a staurosporinederivative having an IC₅₀ of 70 nM for inhibition of in vitro kinaseactivity of MNK1. CGP57380 is a low molecular weight selective,non-cytotoxic inhibitor of MNK2 (MNK2a or MNK2b) or of MNK1: Theaddition of CGP57380 to cell culture cells, transfected with MNK2 (MNK2aor MNK2b) or MNK1 showed a strong reduction of phosphorylated eIF4E.

WO 2007/147874 describes pyridine and pyrazine derivatives as MNK kinaseinhibitors. WO 2007/104053 describes 8-heteroarylpurines as MNK2inhibitors WO 2006/066937 discloses pyrazolopyrimidine compounds, and WO2006/136402 discloses certain thienopyrimidine compounds, both useful asMNK inhibitors.

DE 10 2007 024 470 and WO 2008/141843 disclose sulfoximine-substitutedquinoline and/or quinazoline derivatives which are claimed to act aserythropoietin-producing hepatoma amplified sequence-receptor kinaseinhibitors.

AIM OF THE PRESENT INVENTION

The aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichare MNK1 and/or MNK2 inhibitors.

Another aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichare potent and selective MNK1 and/or MNK2 inhibitors.

A further aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichhave an inhibiting effect on the kinase activity of MNK1 (MNK1a orMNK1b) and/or MNK2 (MNK2a or MNK2b) and/or variants thereof in vitroand/or in vivo and possess suitable pharmacological and pharmacokineticproperties to use them as medicaments.

A further aim of the present invention is to provide effective MNK1and/or MNK2 inhibitors, in particular for the treatment of metabolicdisorders, for example metabolic diseases, inflammatory diseases,cancer, neurodegenerative diseases and their consecutive complicationand disorders.

Still a further aim of the present invention is to provide effectiveMNK1 and/or MNK2 inhibitors, in particular for the treatment ofmetabolic disorders, for example diabetes, dyslipidemia and/or obesityand their consecutive complication and disorders.

A further aim of the present invention is to provide methods fortreating a disease or condition mediated by the inhibition of the kinaseactivity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) and/orvariants thereof in a patient.

A further aim of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further aim of the present invention is to provide a combination of atleast one compound according to the invention with one or moreadditional therapeutic agents.

A further aim of the present invention is to provide methods for thesynthesis of new compounds, in particular sulfoximine substitutedquinazoline derivatives.

A further aim of the present invention is to provide starting and/orintermediate compounds suitable in methods for the synthesis of newcompounds.

Further aims of the present invention become apparent to the one skilledin the art by the description hereinbefore and in the following and bythe examples.

OBJECT OF THE INVENTION

It has now been found that the compounds according to the inventiondescribed in more detail hereinafter have surprising and particularlyadvantageous properties, in particular as MNK1 and/or MNK2 inhibitors.

The present invention concerns compounds of the general formula I:

whereinAr is selected from the group Ar-G1 consisting of:

-   -   wherein X is CH or N;    -   R³ is H, halogen, CN or —C(═O)—NH₂; and    -   R⁴ is selected from the group R⁴-G1 consisting of:

-   -   wherein R⁷ is selected from a group consisting of H, CN,        C₁₋₆-alkyl, —O—(C₁₋₃-alkyl), C₂₋₄-alkynyl, C₃₋₇-cycloalkyl        heterocyclyl, —(C₁₋₃-alkyl)-heterocyclyl,        —(C₁₋₃-alkyl)-O-heterocyclyl aryl, —(C₁₋₃-alkyl)-aryl, 5- or        6-membered heteroaryl, —(C₁₋₃-alkyl)-heteroaryl, —COOH,        —(C═O)—O—(C₁₋₆-alkyl), —(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and        —(C═O)—NR^(N1)R^(N2);    -   wherein R^(N1) is H or C₁₋₃-alkyl; and    -   R^(N2) is selected from a group consisting of H, C₁₋₆-alkyl,        C₂₋₅-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,        —(C₁₋₃-alkyl)-heterocyclyl, —(C₁₋₃-alkyl)-aryl and        —SO₂—(C₁₋₃-alkyl);    -   or R^(N1) and R^(N2) together with the N-atom to which they are        attached form a azetidinyl, pyrrolidinyl, piperidinyl,        4-oxo-piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,        1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl or        1-imino-1,4-thiazinane 1-oxide ring, which may be substituted        with one OH, C₁₋₃-alkyl or —O—C₁₋₃-alkyl; and        -   wherein in the definition of R⁴, each heterocyclyl is            selected from a group consisting of 4-, 5- or 6-membered            saturated monocyclic ring systems containing 1, 2 or 3            heteroatoms independently of each other selected from the            group consisting on O, S, N and NH, wherein one —CH₂— group            may be replaced by a —C(═O)— group and wherein each            heterocyclyl group is optionally substituted with            C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each aryl is phenyl or            naphthyl;        -   wherein in the definition of R⁴, each heteroaryl is selected            from a group consisting of 5- or 6-membered monocyclic            heteroaromatic ring systems containing 1, 2 or 3 heteroatoms            independently of each other selected from the group            consisting on O, S, N and NH and is optionally substituted            with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each alkyl is optionally            substituted with 1 or more F or with one or two substituents            independently selected from the group consisting of CN, OH,            —O—(C₁₋₃-alkyl), —O-tetrahydrofuranyl, NH₂,            —NH—(C═O)—(C₁₋₃-alkyl), —NH—(C═O)—NH—(C₁₋₃-alkyl) or            —NH—SO₂—(C₁₋₃-alkyl); and        -   wherein in the definition of R⁴, each cycloalkyl is            optionally substituted with 1 or more F or one CN, OH, CF₃,            —O—(C₁₋₃-alkyl) or ═O; and            R⁸ and R⁹ are independently of each other selected from the            group consisting of:            H and C₁₋₃-alkyl optionally substituted with 1-3 F or one OH            or NH₂;            R¹ is selected from the group R¹-G1 consisting of:

-   -   wherein R⁵ is selected from the group consisting of:        -   a) C₁₋₅-alkyl, which is optionally substituted with            —O—(C₁₋₃-alkyl), cycloalkyl, —O-heterocyclyl,            C₃₋₇-cycloalkyl, heterocyclyl or phenyl,            -   wherein each alkyl group is optionally substituted with                one or more F; and        -   b) C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₃₋₇-cycloalkyl,            heterocyclyl, heteroaryl, and aryl; and    -   R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F,    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 3 to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one additional heteroatom selected from the group        consisting of O, S and NR^(N),        -   wherein R^(N) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—(C₁₋₃-alkyl)-O—(C₁₋₄-alkyl),            —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl), —C(═O)—N(C₁₋₃-alkyl)₂ or            —SO₂(C₁₋₄-alkyl);    -   and wherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶        together with the sulfur atom to which they are attached may        each be independently substituted with halogen, CN, OH, NH₂,        —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, —NH—C(═O)—(C₁₋₄-alkyl),        —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—C(═O)—NH₂,        —NH—C(═O)—NH—(C₁₋₄-alkyl), —NH—C(═O)—N(C₁₋₄-alkyl)₂,        —N(C₁₋₄-alkyl)-C(═O)—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—O—(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)-C(═O)—NH₂,        —N(C₁₋₄-alkyl)-O(═O)—NH—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂, —O—(C₁₋₄-alkyl),        C₁₋₆-alkyl, C₃₋₇-cycloalkyl, heterocylcyl, heteroaryl,        —C(═O)—NH₂, —C(═O)—NH(C₁₋₄-alkyl), —C(═O)—N(C₁₋₄-alkyl)₂, —COOH,        —C(═O)—O—(C₁₋₄-alkyl), —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl);        —SO—(C₁₋₄-alkyl) or —SO₂—(C₁₋₄-alkyl); and        R² is selected from the group R²-G1 consisting of halogen, CN,        OH, NH₂, C₁₋₃-alkyl, C₂₋₃-alkenyl, C₂₋₃-alkynyl,        C₃₋₅-cycloalkyl, —O—(C₁₋₃-alkyl), —O-cyclopropyl and        —S—C₁₋₃-alkyl, wherein each alkyl group is optionally        substituted with one or more F; and    -   wherein, if not otherwise specified, each alkyl group in the        above definitions is linear or branched and may be substituted        with one to three F;        including any tautomers and stereoisomers thereof,        or a salt thereof        or a solvate or hydrate thereof.

If not specified otherwise, any alkyl moiety mentioned in thisapplication may be straight-chained or branched and may be substitutedwith one to three F.

In a further aspect the present invention relates to processes forpreparing a compound of general formula I and to new intermediatecompounds in these processes.

A further aspect of the invention relates to a salt of the compounds ofgeneral formula I according to this invention, in particular to apharmaceutically acceptable salt thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula I orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are influenced by the inhibition of thekinase activity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b)and/or variants thereof in a patient in need thereof characterized inthat a compound of general formula I or a pharmaceutically acceptablesalt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder in a patient in needthereof characterized in that a compound of general formula I or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided the useof a compound of the general formula I or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for a therapeuticmethod as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula I or a pharmaceutically acceptable saltthereof for use in a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition influenced by the inhibition of the kinase activityof MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) and/or variantsthereof in a patient that includes the step of administering to thepatient in need of such treatment a therapeutically effective amount ofa compound of the general formula I or a pharmaceutically acceptablesalt thereof in combination with a therapeutically effective amount ofone or more additional therapeutic agents.

In a further aspect this invention relates to a use of a compound of thegeneral formula I or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment of diseases or conditions which are influenced by theinhibition of the kinase activity of MNK1 (MNK1a or MNK1b) and/or MNK2(MNK2a or MNK2b) and/or variants thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula I ora pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the groups, residues and substituents,particularly Ar, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(N1) andR^(N2) are defined as above and hereinafter. If residues, substituents,or groups occur several times in a compound, they may have the same ordifferent meanings. Some preferred meanings of individual groups andsubstituents of the compounds according to the invention will be givenhereinafter. Any and each of these definitions may be combined with eachother.

Ar:

Ar-G1:

According to one embodiment, the group Ar is selected from the groupAr-G1 as defined hereinbefore and hereinafter.

Ar-G2:

According to another embodiment, the group Ar is selected from the groupAr-G2 consisting of:

wherein X is CH or N;R³ is H, F, Cl, Br, CN or —C(═O)—NH₂; andR⁴ is as defined hereinbefore or hereinafter.Ar-G3:

According to another embodiment, the group Ar is selected from the groupAr-G3 consisting of:

wherein R⁴ is as defined hereinbefore or hereinafter.Ar-G4:

According to another embodiment, the group Ar is selected from the groupAr-G4 consisting of:

wherein R³ is F, Cl, Br, CN or —C(═O)—NH₂; andR⁴ is as defined hereinbefore or hereinafter.Ar-G5:

According to another embodiment, the group Ar is selected from the groupAr-G5 consisting of:

wherein R³ is F, Cl, CN or —C(═O)—NH₂; andR⁴ is as defined hereinbefore or hereinafter.Ar-G5a:

According to another embodiment, the group Ar is selected from the groupAr-G5a consisting of:

wherein R³ is F, CN or —C(═O)—NH₂; andR⁴ is as defined hereinbefore or hereinafter.Ar-G6:

According to another embodiment, the group Ar is selected from the groupAr-G6 consisting of:

wherein R³ is F or Cl; andR⁴ is as defined hereinbefore or hereinafter.Ar-G6a:

According to another embodiment, the group Ar is selected from the groupAr-G6a consisting of:

wherein R³ is F; andR⁴ is as defined hereinbefore or hereinafter.Ar-G6b:

According to another embodiment, the group Ar is selected from the groupAr-G6b consisting of:

wherein R³ is Cl; andR⁴ is as defined hereinbefore or hereinafter.R⁴:R⁴-G1:

According to one embodiment, the group R⁴ is selected from the groupR⁴-G1 as defined hereinbefore and hereinafter.

R⁴-G1a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G1a consisting of:

-   -   wherein R⁷ is selected from a group consisting of H, CN,        C₁₋₆-alkyl, —O—(C₁₋₃-alkyl), C₂₋₄-alkynyl, C₃₋₇-cycloalkyl        heterocyclyl, —(C₁₋₃-alkyl)-heterocyclyl,        —(C₁₋₃-alkyl)-O-heterocyclyl aryl, —(C₁₋₃-alkyl)-aryl, 5- or        6-membered heteroaryl, —(C₁₋₃-alkyl)-heteroaryl, —COOH,        —(C═O)—O—(C₁₋₆-alkyl), —(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and        —(C═O)—NR^(N1)R^(N2);    -   wherein R^(N1) is H or C₁₋₃-alkyl; and    -   R^(N2) is selected from a group consisting of H, C₁₋₆-alkyl,        C₂₋₅-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,        —(C₁₋₃-alkyl)-heterocyclyl, —(C₁₋₃-alkyl)-aryl and        —SO₂—(C₁₋₃-alkyl);    -   or R^(N1) and R^(N2) together with the N-atom to which they are        attached form a azetidinyl, pyrrolidinyl, piperidinyl,        4-oxo-piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,        1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl or        1-imino-1,4-thiazinane 1-oxide ring, which may be substituted        with one OH, C₁₋₃-alkyl or —O—C₁₋₃-alkyl; and        -   wherein in the definition of R⁴, each heterocyclyl is            selected from a group consisting of 2-oxo-pyrrolidinyl,            2-oxo-piperidinyl, 2-oxo-oxazolidinyl, oxetanyl,            tetrahydrofuranyl, tetrahydropyranyl, [1,4]-dioxanyl and is            optionally substituted with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each aryl is phenyl or            naphthyl;        -   wherein in the definition of R⁴, each heteroaryl is selected            from a group consisting of pyrazolyl, imidazolyl, oxazolyl,            isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl,            pyrimidinyl, pyrazinyl and pyridazinyl and is optionally            substituted with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each alkyl is optionally            substituted with 1 or more F or with one or two substituents            independently selected from the group consisting of CN, OH,            —O—(C₁₋₃-alkyl), —O-tetrahydrofuranyl, NH₂,            —NH—(C═O)—(C₁₋₃-alkyl), —NH—(C═O)—NH—(C₁₋₃-alkyl) or            —NH—SO₂—(C₁₋₃-alkyl); and        -   wherein in the definition of R⁴, each cycloalkyl is            optionally substituted with 1 or more F or one CN, OH, CF₃,            —O—(C₁₋₃-alkyl) or ═O; and            R⁴-G2:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G2 consisting of:

-   -   wherein R⁷ is selected from a group consisting of CN;        C₁₋₆-alkyl; —O—(C₁₋₃-alkyl); C₂₋₄-alkynyl; C₃₋₇-cycloalkyl        heterocyclyl; —(C₁₋₃-alkyl)-heterocyclyl;        —(C₁₋₃-alkyl)-O-heterocyclyl aryl; —(C₁₋₃-alkyl)-aryl; 5- or        6-membered heteroaryl; —(C₁₋₃-alkyl)-heteroaryl; —COOH;        —(C═O)—O—(C₁₋₆-alkyl); —(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and        —(C═O)—NR^(N1)R^(N2);    -   wherein R^(N1) is H or C₁₋₃-alkyl; and    -   R^(N2) is selected from a group consisting of H, C₁₋₆-alkyl,        C₂₋₅-alkynyl, C₃₋₇-cycloalkyl, -heterocyclyl,        —(C₁₋₃-alkyl)-heterocyclyl and —(C₁₋₃-alkyl)-aryl    -   or R^(N1) and R^(N2) together with the N-atom to which they are        attached form a azetidinyl, pyrrolidinyl, piperidinyl,        4-oxo-piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or        1-oxo-thiomorpholinyl ring, which may be substituted with one        OH, C₁₋₃-alkyl or —O—C₁₋₃-alkyl; and        -   wherein in the definition of R⁴, each heterocyclyl is            selected from a group consisting of 2-oxo-pyrrolidinyl,            2-oxo-piperidinyl, 2-oxo-oxazolidinyl, oxetanyl,            tetrahydrofuranyl, tetrahydropyranyl and [1,4]-dioxanyl and            is optionally substituted with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each aryl is phenyl;        -   wherein in the definition of R⁴, each heteroaryl is selected            from a group consisting of pyrazolyl, imidazolyl, oxazolyl,            isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl,            pyrimidinyl, pyrazinyl and pyridazinyl and is optionally            substituted with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each alkyl is optionally            substituted with 1-3 F or with one or two substituents            independently selected from the group consisting of CN, OH,            —O—(C₁₋₃-alkyl), —O-tetrahydrofuranyl, NH₂,            —NH—(C═O)—(C₁₋₃-alkyl), —NH—(C═O)—NH—(C₁₋₃-alkyl) or            —NH—SO₂—(C₁₋₃-alkyl); and        -   wherein in the definition of R⁴, each cycloalkyl is            optionally substituted with 1-3 F or one CN, OH, CF₃ or ═O;            and            R⁸ is selected from the group consisting of H and C₁₋₃-alkyl            optionally substituted with 1-3 F or one OH or NH₂.

Preferably, R⁸ is H, CH₃, CH₂F, CF₃ or CH₂CH₃.

R⁴-G2a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G2a consisting of:

-   -   wherein R⁷ is selected from a group consisting of CN,        C₁₋₆-alkyl, C₃₋₇-cycloalkyl heterocyclyl, phenyl, 5- or        6-membered heteroaryl, —(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and        —(C═O)—NR^(N1)R^(N2);    -   wherein R^(N1) is H or C₁₋₃-alkyl; and    -   R^(N2) is selected from a group consisting of H, C₁₋₆-alkyl,        C₂₋₅-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,        —(C₁₋₃-alkyl)-heterocyclyl and —(C₁₋₃-alkyl)-phenyl;    -   or R^(N1) and R^(N2) together with the N-atom to which they are        attached form a azetidinyl, pyrrolidinyl, piperidinyl,        4-oxo-piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or        1-oxo-thiomorpholinyl ring, which may be substituted with one        OH, C₁₋₃-alkyl or —O—C₁₋₃-alkyl; and        -   wherein in the definition of R⁴, each heterocyclyl is            selected from a group consisting of 2-oxo-pyrrolidinyl,            2-oxo-piperidinyl, 2-oxo-oxazolidinyl, oxetanyl,            tetrahydrofuranyl, tetrahydropyranyl and [1,4]-dioxanyl and            is optionally substituted with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each heteroaryl is selected            from a group consisting of pyrazolyl, imidazolyl, oxazolyl,            isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl,            pyrimidinyl, pyrazinyl and pyridazinyl and is optionally            substituted with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each alkyl is optionally            substituted with 1-3 F or with one or two substituents            independently selected from the group consisting of CN, OH,            —O—(C₁₋₃-alkyl), —O-tetrahydrofuranyl, NH₂,            —NH—(C═O)—(C₁₋₃-alkyl), —NH—(C═O)—NH—(C₁₋₃-alkyl) or            —NH—SO₂—(C₁₋₃-alkyl); and        -   wherein in the definition of R⁴, each cycloalkyl is            optionally substituted with 1-3 F or one CN, OH, CF₃ or ═O;            and            R⁸ is selected from the group consisting of H and C₁₋₃-alkyl            optionally substituted with 1-3 F or one OH or NH₂.

Preferably, R⁸ is H, CH₃, CH₂F, CF₃ or CH₂CH₃.

R⁴-G3:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G3 consisting of:

-   -   wherein R⁷ is selected from a group consisting of CN; C₁₋₄-alkyl        optionally substituted with 1-3 F or with one NH₂ or        —NH—(C═O)—NH—CH₃; C₂₋₃-alkynyl; cyclopropyl optionally        substituted with one CF₃; 2-oxo-pyrrolidinyl; 2-oxo-piperidinyl;        2-oxo-oxazolidinyl; tetrahydrofuranyl; tetrahydropyranyl;        isoxazolyl optionally substituted with CH₃; pyridinyl;        —CH₂-imidazolyl optionally substituted with CH₃;        —(C═O)—O—(C₁₋₃-alkyl), —(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and        —(C═O)—NR^(N1)R^(N2);    -   wherein R^(N1) is H or CH₃ or CH₂CH₃ and    -   R^(N2) is selected from a group consisting of C₁₋₄-alkyl        optionally substituted with 1-3 F or one CN, OH, —O—CH₃;        C₂₋₄-alkynyl; C₃₋₆-cycloalkyl optionally substituted with OH;        oxetanyl; tetrahydrofuranyl; and tetrahydropyranyl;    -   or R^(N1) and R^(N2) together with the N-atom to which they are        attached form a piperidinyl ring; and        -   wherein in the definition of R⁴, each alkyl is optionally            substituted with 1-3 F; and            R⁸ is selected from the group consisting of H and C₁₋₃-alkyl            optionally substituted with 1-3 F.

Preferably, R⁸ is H, CH₃ and CH₂F.

R⁴-G4:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G4 consisting of:

wherein R⁷ is selected from a group consisting of:

-   -   a) heterocyclyl selected from a group consisting of        2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 2-oxo-oxazolidinyl,        oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and        [1,4]-dioxanyl, wherein each heterocyclyl group is optionally        substituted with C₁₋₃-alkyl;    -   b) heteroaryl selected from a group consisting of pyrazolyl,        imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,        thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl        and is optionally substituted with C₁₋₃-alkyl;    -   c) —(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and    -   d) —(C═O)—NR^(N1)R^(N2);    -   wherein R^(N1) is H or CH₃ or CH₂CH₃ and    -   R^(N2) is selected from a group consisting of C₁₋₄-alkyl        optionally substituted with 1-3 F or one CN, OH, —O—CH₃;        C₂₋₄-alkynyl; C₃₋₆-cycloalkyl optionally substituted with OH;        oxetanyl; tetrahydrofuranyl; and tetrahydropyranyl];    -   or R^(N1) and R^(N2) together with the N-atom to which they are        attached form a piperidinyl ring; and    -   wherein in the definition of R⁴, each alkyl is optionally        substituted with 1-3 F; and        R⁸ is selected from the group consisting of H and C₁₋₃-alkyl        optionally substituted with 1-3 F.

Preferably, R⁸ is CH₃.

R⁴-G4a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G4a consisting of:

-   -   wherein R⁷ is selected from a group consisting of        2-oxo-pyrrolidinyl; 2-oxo-piperidinyl; 2-oxo-oxazolidinyl;        tetrahydrofuranyl; tetrahydropyranyl; isoxazolyl optionally        substituted with CH₃; pyridinyl; —CH₂-imidazolyl optionally        substituted with CH₃; —(C═O)—N═S(═O)(C₁₋₃-alkyl)₂, and        —(C═O)—NR^(N1)R^(N2);    -   wherein R^(N1) is H or CH₃ or CH₂CH₃ and    -   R^(N2) is selected from a group consisting of C₁₋₄-alkyl        optionally substituted with 1-3 F or one CN, OH, —O—CH₃;        C₂₋₄-alkynyl; C₃₋₆-cycloalkyl optionally substituted with OH;        oxetanyl; tetrahydrofuranyl; and tetrahydropyranyl;    -   or R^(N1) and R^(N2) together with the N-atom to which they are        attached form a piperidinyl ring; and        -   wherein in the definition of R⁴, each alkyl is optionally            substituted with 1-3 F; and            R⁸ is selected from the group consisting of H and C₁₋₃-alkyl            optionally substituted with 1-3 F.

Preferably, R⁸ is CH₃.

R⁴-G5:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G5 consisting of:

R⁴-G5a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G5a consisting of:

R⁴-G6:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G6 consisting of:

R⁴-G6a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G6a consisting of:

R⁴-G7-I:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G7-I consisting of:

-   -   wherein R⁷ is selected from a group consisting of C₁₋₆-alkyl;        C₃₋₇-cycloalkyl and heterocyclyl: —(C₁₋₃-alkyl)-heterocyclyl:        —(C₁₋₃-alkyl)-O-heterocyclyl: —(C₁₋₃-alkyl)-aryl;        —(C₁₋₃-alkyl)-heteroaryl;        -   wherein each heterocyclyl is selected from a group            consisting of 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl,            2-oxo-oxazolidinyl, oxetanyl, tetrahydrofuranyl,            tetrahydropyranyl and [1,4]-dioxanyl and is optionally            substituted with C₁₋₃-alkyl;        -   wherein each aryl is phenyl;        -   wherein each heteroaryl is selected from a group consisting            of pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl,            thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl            and pyridazinyl and is optionally substituted with            C₁₋₃-alkyl;        -   wherein each alkyl is optionally substituted with 1-3 F or            with one or two substituents independently selected from the            group consisting of CN, OH, —O—(C₁₋₃-alkyl),            —O-tetrahydrofuranyl, NH₂, —NH—(C═O)—(C₁₋₃-alkyl),            —NH—(C═O)—NH—(C₁₋₃-alkyl) or —NH—SO₂—(C₁₋₃-alkyl); and        -   wherein each cycloalkyl is optionally substituted with 1-3 F            or one CN, OH, CF₃ or ═O; and            R⁸ is selected from the group consisting of H and C₁₋₃-alkyl            optionally substituted with 1-3 F or one OH or NH₂.

Preferably, R⁸ is H, CH₃, CH₂F, CF₃ or CH₂CH₃.

R⁴-G7-Ia:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G7-la consisting of:

-   -   wherein R⁷ is selected from a group consisting of C₁₋₆-alkyl;        C₃₋₇-cycloalkyl and heterocyclyl;        -   wherein each heterocyclyl is selected from a group            consisting of 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl,            2-oxo-oxazolidinyl, oxetanyl, tetrahydrofuranyl,            tetrahydropyranyl and [1,4]-dioxanyl and is optionally            substituted with C₁₋₃-alkyl;        -   wherein each alkyl is optionally substituted with 1-3 F or            with one or two substituents independently selected from the            group consisting of CN, OH, —O—(C₁₋₃-alkyl),            —O-tetrahydrofuranyl, NH₂, —NH—(C═O)—(C₁₋₃-alkyl),            —NH—(C═O)—NH—(C₁₋₃-alkyl) or —NH—SO₂—(C₁₋₃-alkyl); and        -   wherein each cycloalkyl is optionally substituted with 1-3 F            or one CN, OH, CF₃ or ═O; and            R⁸ is selected from the group consisting of H and C₁₋₃-alkyl            optionally substituted with 1-3 F or one OH or NH₂.

Preferably, R⁸ is H, CH₃, CH₂F, CF₃ or CH₂CH₃.

R⁴-G7-Ib:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G7-Ib consisting of:

R⁴-G7-II:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G7-II consisting of:

-   -   wherein R⁷ is selected from a group consisting of phenyl and; 5-        or 6-membered heteroaryl;        -   wherein said heteroaryl is selected from a group consisting            of pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl,            thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl            and pyridazinyl and is optionally substituted with            C₁₋₃-alkyl; and        -   wherein each alkyl is optionally substituted with 1-3 F; and            R⁸ is selected from the group consisting of H and C₁₋₃-alkyl            optionally substituted with 1-3 F or one OH or NH₂.

Preferably, R⁸ is H, CH₃, CH₂F, CF₃ or CH₂CH₃.

R⁴-G7-IIa:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G7-IIa consisting of:

-   -   wherein R⁷ is 5- or 6-membered heteroaryl;        -   wherein said heteroaryl is selected from a group consisting            of isoxazolyl and pyridinyl, and is optionally substituted            with C₁₋₃-alkyl; and        -   wherein said alkyl substituent is optionally substituted            with 1-3 F; and            R⁸ is selected from the group consisting of H and C₁₋₃-alkyl            optionally substituted with 1-3 F or one OH or NH₂.

Preferably, R⁸ is H, CH₃, CH₂F, CF₃ or CH₂CH₃.

R⁴-G7-IIb:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G7-IIb consisting of:

R⁴-G7-III:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G7-III consisting of:

-   -   wherein R⁷ is selected from a group consisting of CN;        —(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and —(C═O)—NR^(N1)R^(N2);    -   wherein R^(N1) is H or C₁₋₃-alkyl; and    -   R^(N2) is selected from a group consisting of H, C₁₋₆-alkyl,        C₂₋₅-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,        —(C₁₋₃-alkyl)-heterocyclyl and —(C₁₋₃-alkyl)-aryl;    -   or R^(N1) and R^(N2) together with the N-atom to which they are        attached form a azetidinyl, pyrrolidinyl, piperidinyl,        4-oxo-piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or        1-oxo-thiomorpholinyl ring, which may be substituted with one        OH, C₁₋₃-alkyl or —O—C₁₋₃-alkyl; and        -   wherein in the definition of R⁴, each heterocyclyl is            selected from a group consisting of 2-oxo-pyrrolidinyl,            2-oxo-piperidinyl, 2-oxo-oxazolidinyl, oxetanyl,            tetrahydrofuranyl, tetrahydropyranyl and [1,4]-dioxanyl and            is optionally substituted with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each aryl is phenyl;        -   wherein in the definition of R⁴, each alkyl is optionally            substituted with 1-3 F or with one or two substituents            independently selected from the group consisting of CN, OH,            —O—(C₁₋₃-alkyl), —O-tetrahydrofuranyl, NH₂,            —NH—(C═O)—(C₁₋₃-alkyl), —NH—(C═O)—NH—(C₁₋₃-alkyl) or            —NH—SO₂—(C₁₋₃-alkyl); and        -   wherein in the definition of R⁴, each cycloalkyl is            optionally substituted with 1-3 F or one CN, OH, CF₃ or ═O;            and            R⁸ is selected from the group consisting of H and C₁₋₃-alkyl            optionally substituted with 1-3 F or one OH or NH₂.

Preferably, R⁸ is H, CH₃, CH₂F, CF₃ or CH₂CH₃.

R⁴-G7-IIIa:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G7-IIIa consisting of:

-   -   wherein R⁷ is selected from a group consisting of CN;        —(C═O)—N═S(═O)(C₁₋₂-alkyl)₂ and —(C═O)—NR^(N1)R^(N2);    -   wherein R^(N1) is H or CH₃; and    -   R^(N2) is selected from a group consisting of H, C₁₋₆-alkyl,        C₂₋₅-alkynyl, C₃₋₇-cycloalkyl and heterocyclyl;    -   or R^(N1) and R^(N2) together with the N-atom to which they are        attached form a azetidinyl, pyrrolidinyl, piperidinyl,        4-oxo-piperidinyl or piperazinyl, ring, which may be substituted        with one OH, C₁₋₃-alkyl or —O—C₁₋₃-alkyl; and        -   wherein in the definition of R⁴, each heterocyclyl is            selected from a group consisting of 2-oxo-pyrrolidinyl,            2-oxo-piperidinyl, 2-oxo-oxazolidinyl, oxetanyl,            tetrahydrofuranyl, tetrahydropyranyl and [1,4]-dioxanyl and            is optionally substituted with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each alkyl is optionally            substituted with 1-3 F or with one or two substituents            independently selected from the group consisting of CN, OH,            —O—(C₁₋₃-alkyl; and        -   wherein in the definition of R⁴, each cycloalkyl is            optionally substituted with 1-3 F or one OH; and            R⁸ is selected from the group consisting of H and C₁₋₃-alkyl            optionally substituted with 1-3 F or one OH or NH₂.

Preferably, R⁸ is H, CH₃, CH₂F, CF₃ or CH₂CH₃.

Preferably, R^(N1) is H.

R⁴-G7-IIIb:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G7-IIIb consisting of:

R⁴-G7-IIIc:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G7-IIIc consisting of:

R¹:R¹-G1:

According to one embodiment, the group R¹ is selected from the groupR¹-G1 as defined hereinbefore and hereinafter.

R¹-G2:

According to another embodiment, the group R¹ is selected from the groupR¹-G2 consisting of:

-   -   wherein R⁵ is selected from the group consisting of:        -   a) C₁₋₄-alkyl, which is optionally substituted with            —O—(C₁₋₃-alkyl), —O—C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl, or            phenyl,            -   wherein each alkyl group is optionally substituted with                one or more F; and        -   b) C₃₋₇-cycloalkyl, pyridinyl, and phenyl; and    -   R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F;    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 3- to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one additional heteroatom selected from the group        consisting of O, S and NR^(N),        -   wherein R^(N) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—(C₁₋₃-alkyl)-O—(C₁₋₄-alkyl),            —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl), —C(═O)—N(C₁₋₃-alkyl)₂ or            —SO₂(C₁₋₄-alkyl);    -   and wherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶        together with the sulfur atom to which they are attached may        each be independently substituted with F, Cl, Br, CN, OH, NH₂,        —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, —NH—C(═O)—(C₁₋₄-alkyl),        —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—C(═O)—NH₂,        —NH—C(═O)—NH—(C₁₋₄-alkyl), —NH—C(═O)—N(C₁₋₄-alkyl)₂,        —N(C₁₋₄-alkyl)-C(═O)—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—O—(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)-C(═O)—NH₂,        —N(C₁₋₄-alkyl)-C(═O)—NH—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂, —O—(C₁₋₄-alkyl),        C₁₋₆-alkyl, C₃₋₇-cycloalkyl, piperidinyl, piperazinyl,        morpholinyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl,        pyrazinyl, pyridazinyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄-alkyl),        —C(═O)—N(C₁₋₄-alkyl)₂, —COOH, —C(═O)—O—(C₁₋₄-alkyl),        —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl); —SO—(C₁₋₄-alkyl) or        —SO₂—(C₁₋₄-alkyl).

Preferably, R¹ is selected from the group consisting of:

-   -   wherein R⁵ is selected from the group consisting of:        -   a) C₁₋₃-alkyl, which is optionally substituted with            —O—(C₁₋₃-alkyl), cycloalkyl, C₃₋₇-cycloalkyl, or phenyl,            -   wherein each alkyl group is optionally substituted with                one or more F; and        -   b) C₃₋₇-cycloalkyl, tetrahydropyranyl, pyridinyl, and            phenyl; and    -   R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F;    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one additional heteroatom selected from the group        consisting of O, S and NR^(N),        -   wherein R^(N) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—(C₁₋₃-alkyl)-O—(C₁₋₄-alkyl),            —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl), —C(═O)—N(C₁₋₃-alkyl)₂ or            —SO₂(C₁₋₄-alkyl).            R¹-G3:

According to another embodiment, the group R¹ is selected from the groupR¹-G3 consisting of:

-   -   wherein R⁵ is selected from the group consisting of C₁₋₄-alkyl,        tetrahydropyranyl, pyridinyl and phenyl,        -   wherein the alkyl group is optionally substituted with            —O—CH₃ or phenyl; and    -   R⁶ is C₁₋₃-alkyl;    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 5- or 6-membered saturated heterocycle that        further to the sulfur atom may contain one additional heteroatom        selected from the group consisting of O, S and NR^(N),        -   wherein R^(N) is H, CH₃, —C(═O)—CH₃, —C(═O)—OCH₃,            —C(═O)—CH₂—OCH₃ or —C(═O)—NH—CH₂CH₃.            R¹-G3a:

According to another embodiment, the group R¹ is selected from the groupR¹-G3a consisting of:

-   -   wherein R⁵ is methyl or ethyl; and    -   R⁶ is methyl or ethyl.        R¹-G3b:

According to another embodiment, the group R¹ is selected from the groupR¹-G3b consisting of:

-   -   wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 5- or 6-membered saturated heterocycle that        further to the sulfur atom may contain one additional heteroatom        selected from the group consisting of O and NR^(N),        -   wherein R^(N) is H, CH₃, —C(═O)—CH₃, —C(═O)—OCH₃,            —C(═O)—CH₂—OCH₃ or —C(═O)—NH—CH₂CH₃.            R¹-G4:

According to another embodiment, the group R¹ is selected from the groupR¹-G4 consisting of:

wherein R⁵ is C₁₋₄-alkyl, which is optionally substituted with one ormore F;R⁶ is CH₃ which is optionally substituted with one to three F; andY is CH₂, O, NH or N(C₁₋₃-alkyl).R¹-G5:

According to another embodiment, the group R¹ is selected from the groupR¹-G5 consisting of:

R¹-G5a:

According to another embodiment, the group R¹ is selected from the groupR¹-G5a consisting of:

R¹-G6:

According to another embodiment, the group R¹ is selected from the groupR¹-G6 consisting of:

R¹-G7:

According to another embodiment, the group R¹ is selected from the groupR¹-G7 consisting of:

R²:R²-G1:

According to one embodiment, the group R² is selected from the groupR²-G1 as defined hereinbefore and hereinafter.

R²-G2:

According to another embodiment, the group R² is selected from the groupR²-G2 consisting of F, Cl, Br, CN, C₁₋₃-alkyl, C₃₋₅-cycloalkyl and—O—C₁₋₃-alkyl, wherein each alkyl group is optionally substituted withone to three F.

R²-G3:

According to another embodiment, the group R² is selected from the groupR²-G3 consisting of F, Cl, Br, CH₃, CF₃, cyclopropyl and —O—CH₃.

R²-G4:

According to another embodiment, the group R² is selected from the groupR²-G4 consisting of of F, Cl, CH₃, CF₃ and —O—CH₃.

R²-G5:

According to another embodiment, the group R² is selected from the groupR²-G5 consisting of of F, Cl, CH₃ and CF₃.

R²-G6:

According to another embodiment, the group R² is selected from the groupR²-G6 consisting of CH₃.

The following preferred embodiments of compounds of the formula I aredescribed using generic formulae I.1 to I.5, wherein any tautomers andstereoisomers, solvates, hydrates and salts thereof, in particular thepharmaceutically acceptable salts thereof, are encompassed.

wherein the variables R¹, R², R³, R⁴ and X are defined as hereinbeforeand hereinafter.

Examples of preferred subgeneric embodiments according to the presentinvention are set forth in the following table, wherein each substituentgroup of each embodiment is defined according to the definitions setforth hereinbefore and wherein all other substituents of the formula Iare defined according to the definitions set forth hereinbefore:

Embodiment Ar R⁴ R¹ R² E-1 Ar-G1 R⁴-G1 R¹-G1 R²-G1 E-2 Ar-G1 R⁴-G2 R¹-G2R²-G2 E-3 Ar-G1 R⁴-G2a R¹-G2 R²-G2 E-4 Ar-G2 R⁴-G3 R¹-G3 R²-G3 E-5 Ar-G2R⁴-G3 R¹-G3 R²-G4 E-6 Ar-G2 R⁴-G3 R¹-G3 R²-G6 E-7 Ar-G2 R⁴-G4 R¹-G3R²-G3 E-8 Ar-G2 R⁴-G4 R¹-G4 R²-G4 E-9 Ar-G2 R⁴-G4 R¹-G5 R²-G6 E-10 Ar-G2R⁴-G4 R¹-G6 R²-G6 E-11 Ar-G2 R⁴-G5 R¹-G3 R²-G3 E-12 Ar-G2 R⁴-G5 R¹-G4R²-G4 E-13 Ar-G2 R⁴-G5 R¹-G5 R²-G6 E-14 Ar-G2 R⁴-G5 R¹-G6 R²-G6 E-15Ar-G2 R⁴-G6 R¹-G3 R²-G3 E-16 Ar-G2 R⁴-G6 R¹-G4 R²-G4 E-17 Ar-G2 R⁴-G6R¹-G5 R²-G6 E-18 Ar-G2 R⁴-G6 R¹-G6 R²-G6 E-19 Ar-G3 R⁴-G3 R¹-G3 R²-G3E-20 Ar-G3 R⁴-G3 R¹-G3 R²-G4 E-21 Ar-G3 R⁴-G3 R¹-G3 R²-G6 E-22 Ar-G3R⁴-G4 R¹-G3 R²-G3 E-23 Ar-G3 R⁴-G4 R¹-G4 R²-G4 E-24 Ar-G3 R⁴-G4 R¹-G5R²-G6 E-25 Ar-G3 R⁴-G4 R¹-G6 R²-G6 E-26 Ar-G3 R⁴-G5 R¹-G3 R²-G3 E-27Ar-G3 R⁴-G5 R¹-G4 R²-G4 E-28 Ar-G3 R⁴-G5 R¹-G5 R²-G6 E-29 Ar-G3 R⁴-G5R¹-G6 R²-G6 E-30 Ar-G3 R⁴-G6 R¹-G3 R²-G3 E-31 Ar-G3 R⁴-G6 R¹-G4 R²-G4E-32 Ar-G3 R⁴-G6 R¹-G5 R²-G6 E-33 Ar-G3 R⁴-G6 R¹-G6 R²-G6 E-34 Ar-G4R⁴-G3 R¹-G3 R²-G3 E-35 Ar-G4 R⁴-G3 R¹-G3 R²-G4 E-36 Ar-G4 R⁴-G3 R¹-G3R²-G6 E-37 Ar-G4 R⁴-G4 R¹-G3 R²-G3 E-38 Ar-G4 R⁴-G4 R¹-G4 R²-G4 E-39Ar-G5 R⁴-G4 R¹-G5 R²-G6 E-40 Ar-G5 R⁴-G4 R¹-G6 R²-G6 E-41 Ar-G4 R⁴-G5R¹-G3 R²-G3 E-42 Ar-G4 R⁴-G5 R¹-G4 R²-G4 E-43 Ar-G5 R⁴-G5 R¹-G5 R²-G6E-44 Ar-G5 R⁴-G5 R¹-G6 R²-G6 E-45 Ar-G4 R⁴-G6 R¹-G3 R²-G3 E-46 Ar-G4R⁴-G6 R¹-G4 R²-G4 E-47 Ar-G5 R⁴-G6 R¹-G5 R²-G6 E-48 Ar-G6 R⁴-G3 R¹-G3R²-G3 E-49 Ar-G6 R⁴-G3 R¹-G3 R²-G4 E-50 Ar-G6 R⁴-G3 R¹-G3 R²-G6 E-51Ar-G6 R⁴-G4 R¹-G3 R²-G3 E-52 Ar-G6 R⁴-G4 R¹-G4 R²-G4 E-53 Ar-G6 R⁴-G4R¹-G5 R²-G6 E-54 Ar-G6 R⁴-G4 R¹-G6 R²-G6 E-55 Ar-G6 R⁴-G5 R¹-G3 R²-G3E-56 Ar-G6 R⁴-G5 R¹-G4 R²-G4 E-57 Ar-G6 R⁴-G5 R¹-G5 R²-G6 E-58 Ar-G6R⁴-G5 R¹-G6 R²-G6 E-59 Ar-G6 R⁴-G6 R¹-G3 R²-G3 E-60 Ar-G6 R⁴-G6 R¹-G4R²-G4 E-61 Ar-G6 R⁴-G6 R¹-G5 R²-G6 E-62 Ar-G6 R⁴-G6 R¹-G6 R²-G6 E-63Ar-G6 R⁴-G6 R¹-G6 R²-G6

One embodiment of the invention concerns those compounds of formula I,wherein Ar is selected from the group Ar-G2 consisting of:

wherein X is CH or N;R³ is H, F, Cl, Br, CN or —C(═O)—NH₂; andR⁴ is selected from the group R⁴-G2a consisting of:

-   -   wherein R⁷ is selected from a group consisting of CN,        C₁₋₆-alkyl, C₃₋₇-cycloalkyl heterocyclyl, phenyl, 5- or        6-membered heteroaryl, —(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and        —(C═O)—NR^(N1)R^(N2);    -   wherein R^(N1) is H or C₁₋₃-alkyl; and    -   R^(N2) is selected from a group consisting of H, C₁₋₆-alkyl,        C₂₋₅-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,        —(C₁₋₃-alkyl)-heterocyclyl and —(C₁₋₃-alkyl)-phenyl;    -   or R^(N1) and R^(N2) together with the N-atom to which they are        attached form a azetidinyl, pyrrolidinyl, piperidinyl,        4-oxo-piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or        1-oxo-thiomorpholinyl ring, which may be substituted with one        OH, C₁₋₃-alkyl or —O—C₁₋₃-alkyl; and        -   wherein in the definition of R⁴, each heterocyclyl is            selected from a group consisting of 2-oxo-pyrrolidinyl,            2-oxo-piperidinyl, 2-oxo-oxazolidinyl, oxetanyl,            tetrahydrofuranyl, tetrahydropyranyl and [1,4]-dioxanyl and            is optionally substituted with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each heteroaryl is selected            from a group consisting of pyrazolyl, imidazolyl, oxazolyl,            isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl,            pyrimidinyl, pyrazinyl and pyridazinyl and is optionally            substituted with C₁₋₃-alkyl;        -   wherein in the definition of R⁴, each alkyl is optionally            substituted with 1-3 F or with one or two substituents            independently selected from the group consisting of CN, OH,            —O—(C₁₋₃-alkyl), —O-tetrahydrofuranyl, NH₂,            —NH—(C═O)—(C₁₋₃-alkyl), —NH—(C═O)—NH—(C₁₋₃-alkyl) or            —NH—SO₂—(C₁₋₃-alkyl); and        -   wherein in the definition of R⁴, each cycloalkyl is            optionally substituted with 1-3 F or one CN, OH, OF₃ or ═O;            and            R⁸ is selected from the group consisting of H, CH₃, CH₂F,            OF₃ or CH₂CH₃;            R¹ is selected from the group consisting of:

-   -   wherein R⁵ is methyl or ethyl; and    -   R⁶ is methyl or ethyl;    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 5- or 6-membered saturated heterocycle that        further to the sulfur atom may contain one additional heteroatom        selected from the group consisting of O and NR^(N),        -   wherein R^(N) is H, CH₃, —C(═O)—OH₃, —C(═O)—OCH₃,            —C(═O)—CH₂—OCH₃ or —C(═O)—NH—CH₂CH₃; and            R² is selected from the group R²-G3 consisting of F, Cl, Br,            CH₃, CF₃, cyclopropyl and —O—CH₃;            and the pharmaceutically acceptable salts thereof.

Another embodiment of the invention concerns those compounds of formulaI, wherein Ar is selected from the group Ar-G5 consisting of:

wherein R³ is F, andR⁴ is selected from the group R⁴-G5 consisting of:

R¹ is selected from the group R¹-G6 consisting of:

andR² is selected from the group R²-G6 consisting of CH₃;and the pharmaceutically acceptable salts thereof.

Preferred examples for compounds of formula I are:

and the pharmaceutically acceptable salts thereof.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to the one skilledin the art and described in the literature of organic synthesis.Preferably the compounds are obtained analogously to the methods ofpreparation explained more fully hereinafter, in particular as describedin the experimental section. In some cases the sequence adopted incarrying out the reaction schemes may be varied. Variants of thesereactions that are known to one skilled in the art but are not describedin detail here may also be used. The general processes for preparing thecompounds according to the invention will become apparent to a personskilled in the art on studying the schemes that follow. Startingcompounds are commercially available or may be prepared by methods thatare described in the literature or herein, or may be prepared in ananalogous or similar manner. Before the reaction is carried out anycorresponding functional groups in the compounds may be protected usingconventional protecting groups. These protecting groups may be cleavedagain at a suitable stage within the reaction sequence using methodsfamiliar to a person skilled in the art.

Typical methods of preparing the compounds of the invention aredescribed in the experimental section.

The potent inhibitory effect of the compounds of the invention can bedetermined by in vitro enzyme assays as described in the experimentalsection.

The compounds of the present invention may also be made by methods knownin the art including those described below and including variationswithin the skill of the art.

Compounds of the general formula 1-3, wherein X, R³ and R⁴ are aspreviously defined, can be prepared via the process outlined in Scheme 1using a compound of the general formula 1-1, wherein X and R³ are aspreviously defined, with an alcohol of the general formula 1-2, whereinR⁴ is as previously defined, in presence of a base in appropriatesolvents such as THF or DMF at a temperature between 0° C. and 150° C.As base sodium hydride or lithium hexamethyldisilazane may be used.Hydrogenation of a compound of the general formula 1-3, wherein X, R³and R⁴ are as previously defined, in order to obtain a compound of thegeneral formula 1-4, wherein X, R³ and R⁴ are as previously defined, maybe achieved in the presence of hydrogen and a catalyst such as palladiumor Raney nickel in an appropriate solvent. Hydrogen can be introduced asa gas or stem from a hydrogen source such as ammonium formate.

In Scheme 2 compounds of the general formula 2-3, wherein X, R³ and R⁴are as previously defined, may be obtained by Mitsunobu reaction of acompound with the general formula 2-1, wherein X, R³ are as previouslydefined, with an alcohol of the general formula 2-2, wherein R⁴ is aspreviously defined, in the presence of triphenylphosphine and andialkylazodicarboxylate such as diethylazodicarboxylate,diisopropylazodicarboxylate or di-tert.butylazodiacarboxylate in asolvent such as THF at temperatures between −10° C. and 80° C.,preferrably between 0° C. and 30° C.

4,5,7-substituted quinazolines of the general formula 3-4, wherein X,R¹, R², R³ and R⁴ are as previously defined, may be prepared as shown inscheme 3. Substituted antranilonitriles of the general formula 3-1,wherein R¹ and R² are as previously defined, may react withN,N-dimethylformamide dimethyl acetal under reflux. The resultingformamidines of the general formula 3-2, wherein R¹ and R² are aspreviously defined, may be condensed with primary aromatic amines of thegeneral formula 3-3, wherein X, R³ and R⁴ are as previously defined, inacetic acid (J. Med. Chem., 2010, 53 (7), 2892-2901). Dioxane can beused as cosolvent in this reaction.

The sulphoximine-substituent of the general formula 4-3, wherein R⁵ andR⁶ are as previously defined, may be introduced as shown in Scheme 4 byPd or Cu-catalyzed coupling reactions from the corresponding boronicacid derivatives of the general formula 4-2, wherein R² is as previouslydefined.

The boronic esters of the general formula 4-2, wherein R² is aspreviously defined, may be prepared using a Ir-catalyzed boronylationreaction (Chem. Rev., 2010, 110 (2), 890-931) and coupled with thesulphoximine of the general formula 4-3, wherein R⁵ and R⁶ are aspreviously defined, under Cu-catalysis in a suitable solvent like MeOH(Org. Lett., 2005, 7(13), 2667-2669).

The sulphoximine-substituent of the general formula 5-2, wherein R⁵ andR⁶ are as previously defined, may be introduced as shown in Scheme 5 byPd or Cu-catalyzed coupling reactions from the corresponding bromoderivatives of the general formula 5-1 or 5-4, wherein Ar and R² are aspreviously defined.

For the palladium catalyzed coupling one of the following reactionconditions may be used Pd(OAc)₂, BINAP, Cs₂CO₃ in toluene as solvent (J.Org. Chem., 2000, 65 (1), 169-175), or Pd₂dba₃, 2-(di-t-butylphosphino)biphenyl, NaO^(t)Bu in dioxane or DMF as solvent (cf. WO 2008/141843A1).

In case the R²-substituent of compounds of the general formula 6-2 or6-4 in Scheme 6, wherein Ar, R², R⁵ and R⁶ are as previously defined, islinked via a nitrogen, oxygen or sulphur atom to the ring system, thecorresponding substituent R² may be introduced by nucleophilic aromaticsubstitution from the aryl flouride of the general formula 6-1 or 6-3,wherein Ar, R⁵ and R⁶ are as previously defined, using a suitable basein an inert solvent like Cs₂CO₃ in dioxane or NaH, LiHMDS or DIPEA inNMP.

As shown in Scheme 7 the sulphoximines of the general formula 7-2,wherein R⁵ and R⁶ are as previously defined, may be prepared from thecorresponding sulphoxides of the general formula 7-1, wherein R⁵ and R⁶are as previously defined, by reaction with sodium azide and sulfuricacid (H₂SO₄). A suitable solvent like dichloromethane maybe used.

Alternatively, sulfoximines of the general formula 7-2, wherein R⁵ andR⁶ are as previously defined, may be prepared from the correspondingsulphoxides of the general formula 7-1, wherein R⁵ and R⁶ are aspreviously defined, by reaction with o-mesitylenesulphonylhydroxylamine(MSH) in presence of a suitable solvent like dichlormethane.

As shown in scheme 8 sulphoxides of the general formula 8-1, wherein R⁵and R⁶ are as previously defined, may be react with trifluoracetamide inpresence of Phl(OAc)₂, Rh₂(OAc)₄, and MgO in a suitable solvent likedichlormethane to form compounds of the general formula 8-2, wherein R⁵and R⁶ are as previously defined.

Sulfoximines of the general formula 8-3, wherein R⁵ and R⁶ are aspreviously defined, may be prepared by samponification of compounds ofthe general formula 8-2, wherein R⁵ and R⁶ are as previously defined(Org. Lett., 2004, 6 (8), 1305-1307). Alternatively, other suitableprotecting groups and Iron as catalyst can be utilized (Org. Lett.,2006, 8 (11), 2349-2352).

In scheme 9 a general synthesis of sulfoximines of the general formula9-5, wherein R⁵ and R⁶ are as previously defined, is described.

Starting from the thioethers of the general formula 9-1, wherein R⁵ andR⁶ are as previously defined, the corresponding N-cyano sulfilimines ofthe general formula 9-2, wherein R⁵ and R⁶ are as previously defined,maybe prepared by reaction with cyanamide in the presence of a base likeNaO^(t)Bu or KO^(t)Bu and NBS or I₂ in a suitable solvent like methanol.The sulfilimines of the general formula 9-2, wherein R⁵ and R⁶ are aspreviously defined, are oxidized to the N-cyanosulfoximines of thegeneral formula 9-3, wherein R⁵ and R⁶ are as previously defined. Afterremoval of the N-cyano group the N-trifluoroacetylsulfoximines of thegeneral formula 9-4, wherein R⁵ and R⁶ are as previously defined, may beobtained. After removal of the trifluoroacetyl moiety the NH-freesulfoximines of the general formula 9-5, wherein R⁵ and R⁶ are aspreviously defined, can be obtained (Org. Lett., 2007, 9 (19),3809-3811).

TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one skilled in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula I”, “compound(s) of the invention” and the like denote thecompounds of the formula I according to the present invention includingtheir tautomers, stereoisomers and mixtures thereof and the saltsthereof, in particular the pharmaceutically acceptable salts thereof,and the solvates and hydrates of such compounds, including the solvatesand hydrates of such tautomers, stereoisomers and salts thereof.

The terms “treatment” and “treating” embraces both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refers to the (i) treatment, including preventionof the particular disease or condition, (ii) attenuation, amelioration,or elimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex)” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo-, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking pharmaceutically acceptable acid or base salts thereof.

Salts of acids which are useful, for example, for purifying or isolatingthe compounds of the present invention are also part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example, the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer from 2 to n, eitheralone or in combination with another radical, denotes an acyclic,straight-chain or branched divalent alkyl radical containing from 1 to ncarbon atoms. For example, the term C₁₋₄-alkylene includes —(CH₂)—,—(CH₂—CH₂)—, —(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkenylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenylene includes —CH═CH—,—CH═CH—CH₂—, —CH₂—CH═CH—.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(2-n)-alkynylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynylene includes —C≡C—,—C≡C—CH₂—, —CH₂—C≡C—.

The term “C_(3-n)-carbocyclyl” as used either alone or in combinationwith another radical, denotes a monocyclic, bicyclic or tricyclic,saturated or unsaturated hydrocarbon radical with 3 to n C atoms. Thehydrocarbon radical is preferably nonaromatic. Preferably the 3 to n Catoms form one or two rings. In case of a bicyclic or tricyclic ringsystem the rings may be attached to each other via a single bond or maybe fused or may form a spirocyclic or bridged ring system. For examplethe term C₃₋₁₀-carbocyclyl includes C₃₋₁₀-cycloalkyl,C₃₋₁₀-cycloalkenyl, octahydropentalenyl, octahydroindenyl,decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably the termC_(3-n)-carbocyclyl denotes C_(3-n)-cycloalkyl, in particularC₃₋₇-cycloalkyl.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term bicyclic includes spirocyclic.

The term “C_(3-n)-cycloalkenyl”, wherein n is an integer 3 to n, eitheralone or in combination with another radical, denotes a cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃₋₇-cycloalkenyl includes cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl. More preferably the term “aryl” as used herein, eitheralone or in combination with another radical, denotes phenyl ornaphthyl, most preferably phenyl.

The term “heterocyclyl” means a saturated or unsaturated mono-, bi-,tri- or spirocarbocyclic, preferably mono-, bi- or spirocyclic-ringsystem containing one or more heteroatoms selected from N, O or S(O)_(r)with r=0, 1 or 2, which in addition may have a carbonyl group. Morepreferably the term “heterocyclyl” as used herein, either alone or incombination with another radical, means a saturated or unsaturated, evenmore preferably a saturated mono-, bi- or spirocyclic-ring systemcontaining 1, 2, 3 or 4 heteroatoms selected from N, O or S(O)_(r) withr=0, 1 or 2 which in addition may have a carbonyl group. The term“heterocyclyl” is intended to include all the possible isomeric forms.Examples of such groups include aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl,tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl,piperazinonyl and morpholinonyl.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “heteroaryl” means a mono- or polycyclic, preferably mono- orbicyclic ring system containing one or more heteroatoms selected from N,O or S(O)_(r) with r=0, 1 or 2 wherein at least one of the heteroatomsis part of an aromatic ring, and wherein said ring system may have acarbonyl group. More preferably the term “heteroaryl” as used herein,either alone or in combination with another radical, means a mono- orbicyclic ring system containing 1, 2, 3 or 4 heteroatoms selected fromN, O or S(O)_(r) with r=0, 1 or 2 wherein at least one of theheteroatoms is part of an aromatic ring, and wherein said ring systemmay have a carbonyl group. The term “heteroaryl” is intended to includeall the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

-   -   R^(N)═H or residue attached via a C atom

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

The biological activity of compounds was determined by the followingmethods:

A. MNK2a In Vitro Kinase Assay (Assay 1)

The MNK2a in vitro kinase assay is described in detail in WO2011/104340.

ASSAY SETUP: The inhibition of kinase activity of MNK2a was assessedusing pre-activated GST-MNK2a. The kinase reaction contains 24 μMsubstrate peptide (NH₂-TATKSGSTTKNR-CONH₂ (SEQ ID NO: 1), differing fromSeq. ID No. 5 of WO 2011/104340 by the C-terminal-CONH₂ group), 20 μMATP, 14 nM ligand and 2 nM pre-activated MNK2a. The reaction bufferconditions are 16 mM HEPES/KOH pH 7.4, 8 mM MgCl₂, 0.4 mM DTT, 0.08%(w/v) bovine serum albumin (BSA, Sigma, Germany, cat. no. A3059), 0.008%(w/v) Pluronic F127 (Sigma, Germany, cat. no. P2443), 3% (v/v) DMSO(Applichem, Germany, cat. no. A3006). The kinase reaction is at roomtemperature for 60 min. The kinase reaction is terminated by addition of0.67 reaction volumes of 1 μM antibody in 20 mM HEPES/KOH pH 7.4, 50 mMethylenediaminetetraacetic acid, disodium salt (EDTA, Sigma, Germany,cat. no. E5134), 0.5 mM DTT, 0.05% (w/v) polyoxyethylene-sorbitanmonolaureate (Tween 20, Sigma, Germany, cat. no. P7949). After 1 hequilibration time at room temperature, samples are subjected tofluorescence polarization measurement. The fluorescence polarizationreadout was generated on an Envision multimode reader (PerkinElmer)equipped with a FP Dual Emission filter and mirror set (PerkinElmer2100-4260). Excitation filter 620 nm, S and P polarized emission filters688 nM.

B. MNK2a In Vitro Kinase Assay (Assay 2) ASSAY SETUP: The inhibition ofkinase activity of MNK2a was assessed using pre-activated GST-MNK2a. Thewhite, 384-well OptiPlate F plates were purchased from PerkinElmer. TheADP-Glo Kinase Assay (including ultra pure ATP) was purchased fromPromega (V9103). Activated MNK2a was obtained as described inWO2011/104340. The unlabeled eIF4E peptide (NH₂-TATKSGSTTKNR-CONH₂ (SEQID NO: 1)), differing from Seq. ID No. 5 of WO 2011/104340 by theC-terminal CONH₂ group, was purchased from Thermo Fisher Scientific. Allother materials were of highest grade commercially available. Compoundsare tested in either serial dilutions or single dose concentrations. Thecompound stock solutions are 10 mM in 100% DMSO The serial compounddilutions are prepared in 100% DMSO followed by 1:27.3 intermediatedilution in assay buffer. The final DMSO concentration in assay will be<3%.

In the 384-well plates 3 μl of test compound from the intermediatedilution is mixed with 4 μl of the activated MNK2 enzyme (finalconcentration of 10 nM) and 4 μl of the peptide (final concentration of25 μM)/ultra pure ATP (final concentration of 20 μM), all dissolved inassay buffer. This step is followed by an incubation time of 90 min,then 10 μl of ADP Glo reagent are added, followed by 40 min ofincubation. Then 20 μl of kinase detection reagent are admixed. Theplates are sealed and after an incubation period of 30 min, theluminescence signal is measured in an Envision reader to determine theamount of produced ADP. All incubation steps are performed at roomtemperature. The assay buffer consists of 20 mM HEPES, 2 mM DTT, 0.01%BSA, 20 mM MgCl₂ and 0.1% Pluronic F-127.

Each assay microtiter plate contains wells with vehicle controls insteadof compound (1% DMSO in water) as reference for the high signal (100%CTL, high signal), and wells containing a potent MNK2 inhibitor (final20 μM, 1% DMSO) as reference for low signal (0% CTL, low signal).

The luminescent signal generated is proportional to the ADPconcentration produced and is correlated with activated MNK2 activity.The analysis of the data is performed by the calculation of thepercentage of ATP consumption of activated MNK2 in the presence of thetest compound compared to the consumption of ATP in the presence ofactivated MNK2 without compound.(RLU(sample)−RLU(low control))*100/(RLU(high value)−RLU(lowcontrol))[RLU=relative luminescence units]

An inhibitor of the MNK2 enzyme will give values between 100% CTL (noinhibition) and 0% CTL (complete inhibition). Values of more than 100%CTL are normally related to compound/sample specific physico-chemicalproperties (e.g. solubility, light absorbance, fluorescence).

IC50 values based on dose response curves are calculated with theAssayExplorer software.

C. MNK1 In Vitro Kinase Assay (Assay 3)

MNK1 Data can be obtained from the MNK1 Z′-LYTE® assay. The MNK1Z′-LYTE® screening protocol and assay conditions are also described onwww.invitrogen.com.

The assay is described as follows:

The Z′-LYTE® biochemical assay employs a fluorescence-based,coupled-enzyme format and is based on the differential sensitivity ofphosphorylated and non-phosphorylated peptides to proteolytic cleavage.The peptide substrate is labeled with two fluorophores—one at eachend—that make up a FRET pair.

In the primary reaction, the kinase transfers the gamma-phosphate of ATPto a single tyrosine, serine or threonine residue in a syntheticFRET-peptide. In the secondary reaction, a site-specific proteaserecognizes and cleaves non-phosphorylated FRET-peptides. Phosphorylationof FRET-peptides suppresses cleavage by the Development Reagent.Cleavage disrupts FRET between the donor (i.e., coumarin) and acceptor(i.e., fluorescein) fluorophores on the FRET-peptide, whereas uncleaved,phosphorylated FRET-peptides maintain FRET. A ratiometric method, whichcalculates the ratio (the Emission Ratio) of donor emission to acceptoremission after excitation of the donor fluorophore at 400 nm, is used toquantitate reaction progress, as shown in the equation below.Emission Ratio=Coumarin Emission (445 nm)/Fluorescein Emission (520 nm)

ASSAY SETUP: The inhibition of kinase activity of MNK1a was assessedusing pre-activated GST-MNK1a. The 2×MKNK1 (MNK1) mixture is prepared in50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 4 mM MnCl₂, 1 mM EGTA, 2mM DTT. The final 10 μL Kinase Reaction consists of 13.5-54 ng MKNK1(MNK1) and 2 μM Ser/Thr 07 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mMMgCl₂, 2 mM MnCl₂, 1 mM EGTA, 1 mM DTT. After the 1 hour Kinase Reactionincubation, 5 μL of a 1:32768 dilution of Development Reagent A isadded.

Assay Conditions

Test Compounds:

The Test Compounds are screened in 1% DMSO (final) in the well.

Peptide/Kinase Mixtures:

All Peptide/Kinase Mixtures are diluted to a 2× working concentration inthe MNK1 Kinase Buffer.

ATP Solution:

All ATP Solutions are diluted to a 4× working concentration in KinaseBuffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA).

Development Reagent Solution:

The Development Reagent is diluted in Development Buffer

Assay Protocol:

Bar-coded Corning, low volume NBS, 384-well plate (Corning Cat. #3676)

1. 2.5 μL—4× Test Compound

2. 5 μL—2× Peptide/Kinase Mixture

3. 2.5 μL—4×ATP Solution

4. 30-second plate shake

5. 60-minute Kinase Reaction incubation at room temperature

6. 5 μL—Development Reagent Solution

7. 30-second plate shake

8. 60-minute Development Reaction incubation at room temperature

9. Read on fluorescence plate reader and analyze the data

Data Analysis

The following equations are used for each set of data points:

Correction for Background Fluorescence: FI_(Sample)-FI_(TCFl Ctl)

Emission Ratio (using values corrected for backgroundfluorescence):Coumarin

Emission (445 nm)/Fluorescein Emission (520 nm)

% Phosphorylation (% Phos):1−((Emission Ratio×F₁₀₀%)−C_(100%))/((C_(0%)−C_(100%))+[EmissionRatio×(F_(100%)−F_(0%))])*100%% Inhibition:1−(% Phos_(Sample)/% Phos_(0% Inhibition Ctl))*100FI=Fluorescence IntensityC_(100%)=Average Coumarin emission signal of the 100% Phos. ControlC_(0%)=Average Coumarin emission signal of the 0% Phos. ControlF_(100%)=Average Fluorescein emission signal of the 100% Phos. ControlF_(0%)=Average Fluorescein emission signal of the 0% Phos. ControlGraphing Software

SelectScreen® Kinase Profiling Service uses XLfit from IDBS. The doseresponse curve is curve fit to model number 205 (sigmoidal dose-responsemodel). If the bottom of the curve does not fit between −20% & 20%inhibition, it is set to 0% inhibition. If the top of the curve does notfit between 70% and 130% inhibition, it is set to 100% inhibition.

The activity of MNK proteins can be assayed also by other in vitrokinase assay formats. For example, suitable kinase assays have beendescribed in the literature in Knauf et al., Mol Cell Biol. 2001 August;21(16):5500-11 or in Scheper et al., Mol Cell Biol. 2001 February;21(3):743-54. In general, MNK kinase assays can be performed such that aMNK substrate such as a protein or a peptide, which may or may notinclude modifications as further described below, or others arephosphorylated by MNK proteins having enzymatic activity in vitro. Theactivity of a candidate agent can then be determined via its ability todecrease the enzymatic activity of the MNK protein. The kinase activitymay be detected by change of the chemical, physical or immunologicalproperties of the substrate due to phosphorylation.

In one example, the kinase substrate may have features, designed orendogenous, to facilitate its binding or detection in order to generatea signal that is suitable for the analysis of the substratesphosphorylation status. These features may be, but are not limited to, abiotin molecule or derivative thereof, a glutathione-S-transferasemoiety, a moiety of six or more consecutive histidine residues (SEQ IDNO: 2), an amino acid sequence or hapten to function as an epitope tag,a fluorochrome, an enzyme or enzyme fragment. The kinase substrate maybe linked to these or other features with a molecular spacer arm toavoid steric hindrance.

In another example the kinase substrate may be labelled with afluorophore. The binding of the reagent to the labelled substrate insolution may be followed by the technique of fluorescence polarizationas it is described in the literature. In a variation of this example, afluorescent tracer molecule may compete with the substrate for theanalyte to detect kinase activity by a technique which is know to thoseskilled in the art as indirect fluorescence polarization.

In yet another example, radioactive gamma-ATP is used in the kinasereaction, and the effect of the test agent on the incorporation ofradioactive phosphate in the test substrate is determined relative tocontrol conditions.

It has been shown that the compounds of the invention exhibit low IC₅₀values in in vitro biological screening assays for inhibition of MNK 1and/or MNK 2 kinase activity. The following table contains the testresults for exemplary compounds.

E. Biological Data

TABLE 1 Biological data of the compounds of the present invention asobtained in assay 2. MNK2 IC50 Example [nM] 1.001 17 nM 1.002 6 nM 1.0031 nM 1.004 3 nM 1.005 2 nM 1.006 5 nM 1.007 8 nM 1.008 8 nM 1.009 26 nM1.010 17 nM 1.011 2 nM 1.012 6 nM 1.013 2 nM 1.014 5 nM 1.015 54 nM1.016 1 nM 1.017 12 nM 1.018 6 nM 1.019 1 nM 1.020 7 nM 1.021 1 nM 1.0223 nM 1.023 8 nM 2.001 5 nM 2.002 6 nM 2.003 13 nM 2.004 6 nM 2.005 1 nM2.006 2 nM 2.007 3 nM 2.008 1 nM 2.009 1 nM 2.010 11 nM 2.011 2 nM 2.01228 nM 2.013 2 nM 2.014 2 nM 2.015 190 nM 2.016 1 nM 2.017 2 nM 2.018 1nM 2.019 1 nM 2.020 3 nM 2.021 2 nM 2.022 2 nM 2.023 2 nM 2.024 3 nM2.025 7 nM 2.026 1 nM 2.028 3 nM 2.029 4 nM 2.030 4 nM 2.031 10 nM 2.0321 nM 2.033 4 nM 2.034 1 nM 2.035 2 nM 2.036 4 nM 2.037 2 nM 2.038 3 nM2.039 3 nM 2.040 18 nM 2.041 1 nM 2.042 5 nM 2.043 2 nM 2.044 1 nM 2.0451 nM 2.046 3 nM 2.047 3 nM 2.048 2 nM 3.001 2 nM 3.002 8 nM 3.003 2 nM3.004 17 nM 3.005 1 nM 3.006 1 nM 3.007 9 nM 3.008 5 nM 3.009 7 nM 3.01023 nM 3.011 2 nM 3.012 23 nM 3.013 8 nM 3.014 8 nM 3.015 3 nM 3.016 2 nM3.017 138 3.018 1 nM 3.019 24 nM 3.020 n.D. 3.021 2 nM 3.022 2 nM 3.02342 nM 3.024 16 nM 3.025 n.D. 3.026 4 nM 3.027 2 nM 3.028 6 nM 3.029 17nM 3.030 8 nM 3.031 5 nM 3.032 16 nM 3.033 2 nM 3.034 58 nM 3.035 37 nM3.036 9 nM 3.037 3 nM 3.038 2 nM 3.039 1 nM 3.040 6 nM 3.041 33 nM 3.04215 nM 3.043 5 nM 3.044 63 nM 3.045 10 nM 3.046 2 nM 3.047 1 nM 3.048 11nM 3.049 2 nM 3.050 32 nM 3.051 3 nM 3.052 3 nM 3.053 2 nM 3.054 1 nM3.055 3 nM 4.001 5 nM 4.002 5 nM 4.003 2 nM 4.004 6 nM 4.005 28 nM 4.0065 nM 4.007 2 nM 4.008 2 nM 4.009 2 nM 4.010 4 nM 4.011 24 nM 4.012 34 nM4.013 5 nM 4.014 3 nM 4.015 2 nM 4.016 20 nM 4.017 9 nM 4.018 4 nM 4.0196 nM 4.020 4 nM 4.021 12 nM 4.022 10 nM 4.023 5 nM 4.024 3 nM 4.025 3 nM4.026 3 nM 4.027 1 nM 4.028 4 nM 4.029 3 nM 4.030 11 nM 4.031 8 nM 4.03256 nM 4.033 2 nM 4.034 3 nM 4.035 66 nM 4.036 1 nM 4.037 28 nM 4.038 27nM 4.039 1 nM 4.040 2 nM 4.041 7 nM 4.042 1 nM 4.043 2 nM 4.044 3 nM4.045 3 nM 4.046 15 nM 4.047 5 nM 4.048 2 nM 4.049 19 nM 4.050 1 nM4.051 5 nM 4.052 3 nM 4.053 16 nM 4.054 9 nM 4.055 14 nM 4.056 25 nM4.057 2 nM 4.058 3 nM 4.059 4 nM 4.060 2 nM 4.061 13 nM 4.062 13 nM4.063 10 nM 4.064 8 nM 4.065 9 nM 4.066 9 nM 4.067 3 nM 4.068 4 nM 4.0696 nM 4.070 7 nM 4.071 1 nM 4.072 3 nM 4.073 13 nM 4.074 1 nM 4.075 9 nM4.076 4 nM 4.077 2 nM 4.078 2 nM 4.079 1 nM 4.080 2 nM 4.081 2 nM 4.0822 nM 4.083 8 nM 4.084 2 nM 4.085 2 nM 4.086 2 nM 4.087 2 nM 4.088 2 nM4.089 1 nM 4.090 1 nM 4.091 1 nM 4.092 2 nM 4.093 1 nM 4.094 1 nM 4.0952 nM 4.096 1 nM 4.097 1 nM 4.098 4 nM 4.099 2 nM 4.100 2 nM 4.101 3 nM4.102 2 nM 4.103 1 nM 4.104 1 nM 4.105 2 nM 4.106 2 nM 4.107 2 nM 4.1082 nM 4.109 2 nM 4.110 2 nM 4.111 1 nM 4.112 2 nM 4.113 1 nM 4.114 5 nM4.115 2 nM 4.116 2 nM 4.117 3 nM 4.118 3 nM 4.119 2 nM 4.120 2 nM 4.1215 nM 4.122 1 nM 4.123 3 nM 4.124 1 nM 4.125 1 nM 4.126 2 nM 4.127 2 nM4.128 2 nM 4.129 2 nM 4.130 3 nM 4.131 1 nM 4.132 1 nM 4.133 4 nM 4.1343 nM 4.135 2 nM 4.136 1 nM 4.137 1 nM 4.138 1 nM 4.139 1 nM 4.140 1 nM4.141 1 nM 4.142 2 nM 4.143 2 nM 4.144 2 nM 4.145 2 nM 4.146 4 nM 4.1473 nM 5.001 1 nM 5.002 7 nM 5.003 83 nM 5.004 2 nM 5.005 2 nM 5.006 29 nM5.007 4 nM 5.008 2 nM 5.009 35 nM 5.010 28 nM 5.011 99 nM 5.012 56 nM5.013 2 nM 6.001 5 nM 6.002 2 nM 6.003 4 nM 6.004 3 nM 7.001 1 nM 7.0026 nM 7.003 2 nM 7.004 67 nM 7.005 3 nM 7.006 3 nM 7.007 10 nM 7.008 3 nM7.009 3 nM 7.010 2 nM 7.011 3 nM 7.012 46 nM 7.013 4 nM

TABLE 2 Biological data of selected compounds of the present inventionas obtained in assay 3. MNK1 IC50 # [nM] 1.011 34 nM 1.016 53 nM 1.01954 nM 2.001 228 nM 2.006 71 nM 2.008 25 nM 2.009 49 nM 2.018 34 nM 2.04840 nM 3.001 60 nM 3.031 75 nM 3.039 77 nM 3.049 68 nM 3.054 51 nM 4.03451 nM 4.058 75 nM 4.071 55 nM 4.074 38 nM 4.088 36 nM 4.100 14 nM 4.11821 nM 4.136 29 nM 4.138 27 nM 5.004 66 nM 5.008 39 nM 7.006 164 nM 7.00950 nM 7.010 40 nM

TABLE 3 % Inhibition of MNK1 at a compound concentration of 1 μM asobtained in assay 3 MNK1 # % INH 1.002 59 1.003 95 1.004 79 1.005 981.006 96 1.008 63 1.009 64 1.012 96 1.014 97 1.015 100 1.018 93 1.020 801.021 52 1.022 79 1.023 65 2.002 94 2.003 76 2.004 75 2.005 96 2.010 762.011 94 2.012 102 2.014 99 2.017 90 3.002 80 3.003 73 3.006 70 3.007 963.008 89 3.009 95 3.012 100 3.013 88 3.014 78 3.015 45 3.016 90 3.018 923.019 48 3.021 86 3.022 98 3.026 53 3.027 98 3.028 92 3.029 72 3.030 913.032 26 3.033 56 3.035 89 3.038 86 3.042 78 3.043 82 3.044 49 3.045 783.046 97 3.047 96 3.048 88 3.050 87 3.054 58 4.001 97 4.002 54 4.003 964.005 74 4.008 97 4.009 99 4.010 89 4.011 86 4.012 56 4.013 88 4.014 964.015 102 4.017 73 4.018 99 4.019 92 4.020 98 4.021 92 4.022 85 4.023 994.024 98 4.027 99 4.028 86 4.029 99 4.031 78 4.032 94 4.035 87 4.037 454.038 78 4.040 97 4.041 82 4.042 97 4.044 96 4.045 99 4.047 86 4.048 984.050 100 4.051 82 4.052 94 4.053 80 4.054 95 4.055 62 4.056 74 4.057102 4.059 90 4.060 99 4.061 70 4.062 88 4.063 56 4.064 82 4.065 93 4.06797 4.068 86 4.069 93 4.072 98 4.073 70 4.075 90 4.088 99 4.100 97 4.104100 4.118 99 4.136 93 4.138 64 5.001 97 5.002 88 5.003 38 5.005 95 5.00678 5.007 97 5.009 74 5.010 62 5.011 27 5.012 61 7.001 98 7.002 73 7.003102 7.004 51 7.005 93 7.006 84 7.007 67 7.008 99Method of Treatment

In view of their ability to inhibit the activity of the MNK1 (MNK1a orMNK1b) and/or MNK2 (MNK2a or MNK2b) kinase, the compounds of generalformula I according to the invention, including the corresponding saltsthereof, are theoretically suitable for the treatment of all thosediseases or conditions which may be affected or which are mediated bythe inhibition of the the MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a orMNK2b) kinase.

Accordingly, the present invention relates to a compound of generalformula I as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula I or a pharmaceutical composition according to thisinvention for the treatment and/or prevention of diseases or conditionswhich are mediated by the the inhibition of the the MNK1 (MNK1a orMNK1b) and/or MNK2 (MNK2a or MNK2b) kinase in a patient, preferably in ahuman.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the the inhibition of thethe MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase in amammal that includes the step of administering to a patient, preferablya human, in need of such treatment a therapeutically effective amount ofa compound or a pharmaceutical composition of the present invention.

Diseases and conditions mediated by inhibitors of the the inhibition ofthe the MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinaseembrace metabolic diseases or conditions.

The present invention is directed to compounds which are useful in thetreatment and/or prevention of a disease, disorder and/or conditionwherein the inhibition of the activity of the MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a or MNK2b) kinase is of therapeutic benefit, includingbut not limited to the treatment of metabolic diseases, such as obesity,eating disorders, cachexia, diabetes mellitus, metabolic syndrome,hypertension, coronary heart diseases, hypercholesterolemia,dyslipidemia, osteoarthritis, biliary stones and/or sleep apnea anddiseases related to reactive oxygen compounds (ROS defense) such asdiabetes mellitus, neurodegenerative diseases and cancer.

The pharmaceutical compositions of the invention are particularly usefulfor prophylaxis and treatment of obesity, diabetes mellitus and othermetabolic diseases of the carbohydrate and lipid metabolism as statedabove, in particular diabetes mellitus and obesity.

Thus, in a more preferred embodiment of this invention the use of acompound of the invention for the production of a pharmaceuticalcomposition for the prophylaxis or therapy of metabolic diseases isprovided.

In yet a further aspect of the invention the use of a compound of theinvention for the production of a pharmaceutical composition fortreating or preventing a cytokine mediated disorder such as aninflammatory disease is provided.

The pharmaceutical compositions of the invention are thus useful for theprophylaxis or therapy of inflammatory diseases, in particular chronicor acute inflammation, chronic inflammatory arthritis, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, juvenile rheumatoidarthritis, gouty arthritis; psoriasis, erythrodermic psoriasis, pustularpsoriasis, inflammatory bowel disease, Crohn's disease and relatedconditions, ulcerative colitis, colitis, diverticulitis, nephritis,urethritis, salpingitis, oophoritis, endomyometritis, spondylitis,systemic lupus erythematosus and related disorders, multiple sclerosis,asthma, meningitis, myelitis, encephalomyelitis, encephalitis,phlebitis, thrombophlebitis, chronic obstructive disease (COPD),inflammatory lung disease, allergic rhinitis, endocarditis,osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumaticendocarditis, rheumatic myocarditis, rheumatic mitral valve disease,rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjogren's syndrome, neuroinflammatory disease, sepsis, conjubctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis,oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, goodpasture's disease, crescenticglomerulonephritis, pancreatitis, dermatitis, endomyometritis,myometritis, metritis, cervicitis, endocervicitis, exocervicitis,parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

As already stated above, the compositions of the present invention areparticularly useful for treating or preventing a disease selected fromchronic or acute inflammation, chronic inflammatory arthritis,rheumatoid arthritis, psoriasis, COPD, inflammatory bowel disease,septic shock, Crohn's disease, ulcerative colitis, multiple sclerosisand asthma.

Thus, in a more preferred embodiment of this invention the use of acompound according to the invention for the production of apharmaceutical composition for the prophylaxis or therapy ofinflammatory diseases selected from chronic or acute inflammation,chronic inflammatory arthritis, rheumatoid arthritis, psoriasis, COPD,inflammatory bowel disease, septic shock Crohn's disease, ulcerativecolitis, multiple sclerosis and asthma is provided.

In yet a further aspect of the invention the use of a compound of theinvention for the production of a pharmaceutical composition fortreating or preventing cancer, viral diseases or neurodegenerativediseases is provided.

In a further aspect of the invention the use of a compound of thepresent invention for the production of a pharmaceutical composition forinhibiting the activity of the kinase activity of MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a, MNK2b) or further variants thereof is provided, inparticular for the prophylaxis or therapy of metabolic diseases,hematopoietic disorders, cancer and their consecutive complications anddisorders. Whereby the prophylaxis and therapy of metabolic diseases ofthe carbohydrate and/or lipid metabolism is preferred.

For the purpose of the present invention, a therapeutically effectivedosage will generally be from about 1 to 2000 mg/day, preferably fromabout 10 to about 1000 mg/day, and most preferably from about 10 toabout 500 mg/day, which may be administered in one or multiple doses.

It will be appreciated, however, that specific dose level of thecompounds of the invention for any particular patient will depend on avariety of factors such as age, sex, body weight, general healthcondition, diet, individual response of the patient to be treated timeof administration, severity of the disease to be treated, the activityof particular compound applied, dosage form, mode of application andconcomitant medication. The therapeutically effective amount for a givensituation will readily be determined by routine experimentation and iswithin the skills and judgment of the ordinary clinician or physician.In any case the compound or composition will be administered at dosagesand in a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

It will be appreciated by the person of ordinary skill in the art thatthe compounds of the invention and the additional therapeutic agent maybe formulated in one single dosage form, or may be present in separatedosage forms and may be either administered concomitantly (i.e. at thesame time) or sequentially.

The pharmaceutical compositions of the present invention may be in anyform suitable for the intended method of administration.

The compounds, compositions, including any combinations with one or moreadditional therapeutic agents, according to the invention may beadministered by oral, transdermal, inhalative, parenteral or sublingualroute. Of the possible methods of administration, oral or intravenousadministration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I,optionally in combination with one or more further therapeutic agents,will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. Oral formulations, particularly solid forms such as e.g.tablets or capsules are preferred. The content of the pharmaceuticallyactive compound(s) is advantageously in the range from 0.1 to 90 wt.-%,for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers. Theparticular excipients, carriers and/or diluents that are suitable forthe desired preparations will be familiar to a person skilled in the arton the basis of his specialist knowledge. The preferred ones are thosethat are suitable for the particular formulation and method ofadministration that are desired. The preparations or formulationsaccording to the invention may be prepared using methods known per sethat are familiar to one skilled in the art, such as for example bymixing or combining at least one compound of formula I according to theinvention, or a pharmaceutically acceptable salt of such a compound andone or more excipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsdescribed hereinbefore, in particular associated with metabolic diseasesor conditions such as for example diabetes mellitus, obesity, diabeticcomplications, hypertension, hyperlipidemia. Additional therapeuticagents which are suitable for such combinations include in particularthose which for example potentiate the therapeutic effect of one or moreactive substances with respect to one of the indications mentionedand/or which allow the dosage of one or more active substances to bereduced.

Other active substances which are suitable for such combinationsinclude, for example, antidiabetics like insulin, long and short actinginsulin analogues, sulfonylureas, biguanides, DPP-IV inhibitors, SGLT2inhibitors, 11β-HSD inhibitors, glucokinase activators, AMPK activators,Glp-1 receptor agonists, GlP receptor agonists, DGAT inhibitors,PPARgamma agonists, PPARdelta agonists, and other antidiabetics derivedfrom thiazolidinediones, lipid lowering agents such as statines,fibrates, ion exchange resins nicotinic acid derivatives, or HMG-CoAreductase inhibitors, cardiovascular therapeutics such as nitrates,antihypertensiva such as β-blockers, ACE inhibitors, Ca-channelblockers, angiotensin II receptor antagonists, diuretics, thrombocyteaggregation inhibitors, or antineoplastic agents such as alkaloids,alkylating agents, antibiotics, or antimetabolites, or anti-obesityagents. Further preferred compositions are compositions wherein theadditional therapeutic agent is selected from a histamine antagonist, abradikinin antagonist, serotonin antagonist, leukotriene, ananti-asthmatic, an NSAID, an antipyretic, a corticosteroid, anantibiotic, an analgetic, a uricosuric agent, chemotherapeutic agent, ananti gout agent, a bronchodilator, a cyclooxygenase-2 inhibitor, asteroid, a 5-lipoxygenase inhibitor, an immunosuppressive agent, aleukotriene antagonist, a cytostatic agent, an antineoplastic agent, amTor inhibitor, a Tyrosine kinase inhibitor, antibodies or fragmentsthereof against cytokines and soluble parts (fragments) of cytokinereceptors.

More particularly preferred are compounds such as human NPH insulin,human lente or ultralente insulin, insulin Lispro, insulin Aspart,insulin Glulisine, insulin detemir or insulin Glargine, metformin,phenformin, acarbose, miglitol, voglibose, pioglitazone, rosiglizatone,rivoglitazone, aleglitazar, alogliptin, saxagliptin, sitagliptin,vildagliptin, exenatide, liraglutide, albiglutide, pramlintide,carbutamide, chlorpropamide, glibenclamide (glyburide), gliclazide,glimepiride, glipizide, gliquidone, tolazamide, tolbutamide, atenolol,bisoprolol, metoprolol, esmolol, celiprolol, talinolol, oxprenolol,pindolol, propanolol, bupropanolol, penbutolol, mepindolol, sotalol,certeolol, nadolol, carvedilol, nifedipin, nitrendipin, amlodipin,nicardipin, nisoldipin, diltiazem, enalapril, verapamil, gallopamil,quinapril, captopril, lisinopril, benazepril, ramipril, peridopril,fosinopril, trandolapril, irbesatan, losartan, valsartan, telmisartan,eprosartan, olmesartan, hydrochlorothiazide, piretanid, chlorotalidone,mefruside, furosemide, bendroflumethiazid, triamterene, dehydralazine,acetylsalicylic acid, tirofiban-HCl, dipyramidol, triclopidin,iloprost-trometanol, eptifibatide, clopidogrel, piratecam, abciximab,trapidil, simvastatine, bezafibrate, fenofibrate, gemfibrozil,etofyllin, clofibrate, etofibrate, fluvastatine, lovastatine,pravastatin, colestyramide, colestipol-HCl, xantinol nicotinat, inositolnicotinat, acipimox, nebivolol, glycerolnitrate, isosorbide mononitrate,isosorbide dinitrate, pentaerythrityl tetranitrate, indapamide,cilazepril, urapidil, eprosartan, nilvadipin, metoprolol, doxazosin,molsidormin, moxaverin, acebutolol, prazosine, trapidil, clonidine,vinca alkaloids and analogues such as vinblastin, vincristin, vindesin,vinorelbin, podophyllotoxine derivatives, etoposid, teniposid,alkylating agents, nitroso ureas, N-lost analogues, cycloplonphamid,estamustin, melphalan, ifosfamid, mitoxantron, idarubicin, doxorubicin,bleomycin, mitomycin, dactinomycin, daptomycin, docetaxel, paclitaxel,carboplatin, cisplatin, oxaliplatin, BBR3464, satraplatin, busulfan,treosulfan, procarbazine, dacarbazine, temozolomide, chlorambucil,chlormethine, cyclophosphamide, ifosfamide, melphalan, bendamustine,uramustine, ThioTEPA, camptothecin, topotecan, irinotecan, rubitecan,etoposide, teniposide, cetuximab, panitumumab, trastuzumab, rituximab,tositumomab, alemtuzumab, bevacizumab, gemtuzumab, aminolevulinic acid,methyl aminolevulinate, porfimer sodium, verteporfin, axitinib,bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib,lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib,vandetanib, retinoids (alitretinoin, tretinoin), altretamine, amsacrine,anagrelide, arsenic trioxide, asparaginase (pegaspargase), bexarotene,bortezomib, denileukin diftitox, estramustine, ixabepilone, masoprocol,mitotane, testolactone, tipifarnib, abetimus, deforolimus, everolimus,gusperimus, pimecrolimus, sirolimus, tacrolimus, temsirolimus,antimetabolites such as cytarabin, fluorouracil, fluoroarabin,gemcitabin, tioguanin, capecitabin, combinations such asadriamycin/daunorubicin, cytosine arabinosid/cytarabine, 4-HC, or otherphosphamides.

Other particularly preferred compounds are compounds such as clemastine,diphenhydramine, dimenhydrinate, promethazine, cetirizine, astemizole,levocabastine, loratidine, terfenadine, acetylsalicylic acid, sodoumsalicylate, salsalate, diflunisal, salicylsalicylic acid, mesalazine,sulfasalazine, osalazine, acetaminophen, indomethacin, sulindac,etodolac, tolmetin, ketorolac, bethamethason, budesonide, chromoglycinicacid, dimeticone, simeticone, domperidone, metoclopramid, acemetacine,oxaceprol, ibuprofen, naproxen, ketoprofen, flubriprofen, fenoprofen,oxaprozin, mefenamic acid, meclofenamic acid, pheylbutazone,oxyphenbutazone, azapropazone, nimesulide, metamizole, leflunamide,eforicoxib, lonazolac, misoprostol, paracetamol, aceclofenac,valdecoxib, parecoxib, celecoxib, propyphenazon, codein, oxapozin,dapson, prednisone, prednisolon, triamcinolone, dexibuprofen,dexamethasone, flunisolide, albuterol, salmeterol, terbutalin,theophylline, caffeine, naproxen, glucosamine sulfate, etanercept,ketoprofen, adalimumab, hyaluronic acid, indometacine, proglumetacinedimaleate, hydroxychloroquine, chloroquine, infliximab, etofenamate,auranofin, gold, [²²⁴Ra]radium chloride, tiaprofenic acid,dexketoprofen(trometamol), cloprednol, sodium aurothiomalateaurothioglucose, colchicine, allopurinol, probenecid, sulfinpyrazone,benzbromarone, carbamazepine, lornoxicam, fluorcortolon, diclofenac,efalizumab, idarubicin, doxorubicin, bleomycin, mitomycin, dactinomycin,daptomycin, cytarabin, fluorouracil, fluoroarabin, gemcitabin,tioguanin, capecitabin, adriamydin/daunorubicin, cytosinearabinosid/cytarabine, 4-HC, or other phosphamides, penicillamine, ahyaluronic acid preparation, arteparon, glucosamine, MTX, solublefragments of the TNF-receptor (such as etanercept (Enbrel)) andantibodies against TNF (such as infliximab (Remicade), natalizumab(Tysabri) and adalimumab (Humira)).

EXAMPLES

Preliminary Remarks:

The hereinafter described compounds have been characterized throughtheir characteristic mass after ionisation in a mass-spectrometer andtheir retention time on an analytical HPLC.

LIST OF ABBREVIATIONS

-   ACN Acetonitrile-   AcOH acetic acid-   aq. Aqueous-   BOC tert-butoxy-carbonyl--   ° C. degree celsius-   DCM Dichloromethane-   DEA Diethylamine-   DIPEA N,N-Diisopropylethylamine-   DMF N,N-dimethylformamide-   DMSO Dimethyl sulfoxide-   ESI-MS electrospray ionisation mass spectrometry-   EtOAc ethyl acetate-   EtOH Ethanol-   h Hour-   HATU    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HPLC high performance liquid chromatography-   L Liter-   MeOH Methanol-   min Minute-   mL Milliliter-   MS mass spectrum-   μW Reaction was performed in a microwave-   n.d. not determined-   NH4OH solution of NH₃ in water-   Pd₂dba₃ Tris(dibenzylideneacetone)dipalladium(0)-   psi pound per square inch-   RT room temperature (about 20° C.)-   R_(t) retention time-   TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA Triethylamine-   TF/TFA trifluoroacetic acid-   THF Tetrahydrofuran-   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene    HPLC Methods    HPLC-A:

Agilent 1200 with DA- and MS-detector, XBridge C18_3.0×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol [H2O % Sol Flow [min] 0.1% TFA] [Acetonitrile] [ml/min] 0.097.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.40.0 100.0 3.0HPLC-B:

Agilent 1200 with DA- and MS-Detector, Sunfire C18_3.0×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol [H2O % Sol Flow [min] 0.1% TFA] [Acetonitrile] [ml/min] 0.097.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.40.0 100.0 3.0HPLC-C:

Waters Acquity with DA- and MS-detector and CTC Autosampler, BEHC18_2.1×30 mm, 1.7 μm (Waters), 60° C.

Time % Sol [H2O % Sol Flow [min] 0.1% NH4OH] [Acetonitrile] [ml/min] 0.098.0 2.0 1.5 1.2 0.0 100.0 1.5 1.4 0.0 100.0 1.5 1.45 98.0 2.0 1.5HPLC-D:

Waters 1525 with DA- and MS-detector, Sunfire C18_4.6×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol [H2O % Sol Flow [min] 0.1% TFA] [Acetonitrile] [ml/min] 0.097.0 3.0 4.0 0.15 97.0 3.0 3.0 2.15 0.0 100.0 3.0 2.2 0.0 100.0 4.5 2.40.0 100.0 4.5HPLC-E:

Agilent 1200 with DA- and MS-detector, StableBond C18_3.0×30 mm, 1.8 μm(Agilent), 60° C.

Time % Sol [H2O % Sol Flow [min] 0.1% TFA] [Acetonitrile] [ml/min] 0.097.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.40.0 100.0 3.0HPLC-F:

Waters 1525 with DA- and MS-detector, XBridge C18_4.6×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol [H2O % Sol Flow [min] 0.1% TFA] [Acetonitrile] [ml/min] 0.060.0 40.0 4.0 0.15 60.0 40.0 3.0 2.15 0.0 100.0 3.0 2.2 0.0 100.0 4.52.4 0.0 100.0 4.5HPLC-G:

Waters Acquity with DA- and MS-Detector, XBridge BEH C18_2.1×30 mm, 1.7μm (Waters), 60° C.

Time % Sol [H2O % Sol Flow [min] 0.1% TFA] [Acetonitrile] [ml/min] 0.099.0 1.0 1.6 0.02 99.0 1.0 1.6 1.0 0.0 100.0 1.6 1.1 0.0 100.0 1.6HPLC-H:

Agilent 1200 with DA- and MS-detector, XBridge C18_3×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol [H2O % Sol Flow [min] 0.1% TFA] [Methanol] [ml/min] 0.0 95.05.0 2.2 0.3 95.0 5.0 2.2 1.5 0.0 100.0 2.2 1.55 0.0 100.0 2.9 1.65 0.0100.0 2.9HPLC-I:

Agilent 1100 with DAD, Waters autosampler and MS-detector, SunFireC18_4.6×30 mm, 3.5 μm (Waters), 60° C.

Time % Sol [H2O % Sol Flow [min] 0.1% TFA] [Acetonitrile] [ml/min] 0.098.0 2.0 2.5 1.5 0.0 100.0 2.5 1.8 0.0 100.0 2.5HPLC-J:

Agilent 1200 with DA- and MS-Detector, SunFire C18_3.0×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol [H2O % Sol Flow [min] 0.1% TFA] [Methanol] [ml/min] 0.0 95.05.0 1.8 0.25 95.0 5.0 1.8 1.7 0.0 100.0 1.8 1.75 0.0 100.0 2.5 1.9 0.0100.0 2.5HPLC-K:

Waters Acquity with 3100 MS, XBridge BEH C18_3.0×30 mm, 1.7 μm (Waters),60° C.

Time % Sol [H2O 0.1% % Sol [min] NH4OH] [Acetonitrile] Flow [ml/min] 0.095.0 5.0 1.5 0.7 0.1 99.9 1.5 0.8 0.1 99.9 1.5 0.81 95.0 5.0 1.5 1.195.0 5.0 1.5HPLC-L:

Waters Acquity with DA- and MS-detector, BEH C18_2.1×30 mm, 1.7 μm(Waters), 60° C.

Time % Sol [H2O 0.1% % Sol [min] NH4OH] [Acetonitrile] Flow [ml/min] 0.095.0 5.0 1.5 0.8 0.1 99.9 1.5 0.9 0.1 99.9 1.5HPLC-M:

Agilent 1200 with DA- and MS-detector, XBridge C18_3.0×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol [H2O 0.1% % Sol [min] NH4OH] [Acetonitrile] Flow [ml/min] 0.097.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0 100.0 2.2 1.25 0.0 100.0 3.0 1.40.0 100.0 3.0

Waters Acquity with DA- and MS-detector and CTC autosampler, XBridgeC18_3.0×30 mm, 2.5 μm (Waters), 60° C.

Time % Sol [H2O 0.1% % Sol [min] NH4OH] [Acetonitrile] Flow [ml/min] 0.098.0 2.0 2.0 1.2 0.0 100.0 2.0 1.4 0.0 100.0 2.0HPLC-O:

Waters 1525 with DA- and MS-Detector, Sunfire C18_4.6×30 mm, 2.5 μm(Waters), 60° C.

Time % Sol [H2O 0.1% % Sol [min] TFA] [Acetonitrile] Flow [ml/min] 0.060.0 40.0 4.0 0.15 60.0 40.0 3.0 2.15 0.0 100.0 3.0 2.2 0.0 100.0 4.52.4 0.0 100.0 4.5HPLC-P:

Agilent 1100 with DAD, CTC autosampler and Waters MS-detector, XBridgeC18_4.6×30 mm, 3.5 μm (Waters), 60° C.

Gradient/Solvent % Sol [H2O 0.1% % Sol Flow Time [min] NH4OH][Acetonitrile] [ml/min] 0.0 98.0 2.0 2.5 1.5 0.0 100.0 2.5 1.8 0.0 100.02.5HPLC-Q:

Waters Acquity with 3100 MS, Sunfire C18_2.1×50 mm, 2.5 μm (Waters), 60°C.

Time % Sol [H2O 0.1% % Sol [Acetonitrile Flow [min] TFA] 0.08% TFA][ml/min] 0.0 95.0 5.0 1.5 0.75 0.0 100.0 1.5 0.85 0.0 100.0 1.5HPLC-R:

Waters 1525 with DA- and MS-detector, XBridge C18_4.6×30 mm, 2.5 μm(Waters), 60° C.

% Sol [H2O 0.1% % Sol Flow Time [min] TFA] [Methanol] [ml/min] 0.0 95.05.0 4.0 0.05 95.0 5.0 3.0 2.05 0.0 100.0 3.0 2.1 0.0 100.0 4.5 2.4 0.0100.0 4.5HPLC-S:

Waters 1525 with DA- and MS-detector, XBridge C18_4.6×30 mm, 2.5 μm(Waters), 60° C.

Gradient/Solvent % Sol [H2O 0.1% % Time [min] TFA] Sol [Acetonitrile]Flow [ml/min] 0.0 97.0 3.0 4.0 0.15 97.0 3.0 3.0 2.15 0.0 100.0 3.0 2.20.0 100.0 4.5 2.4 0.0 100.0 4.5HPLC-T:

Agilent 1100 with DA-detector, XBridge C18_3.0×30 mm, 2.5 μm (Waters),60° C.

% Sol % Time [min] [H₂O 0.1% NH₄OH] Sol [Acetonitrile] Flow [ml/min] 0.098.0 2.0 2.0 1.2 0.0 100.0 2.0 1.4 0.0 100.0 2.0HPLC-U:

Agilent 1100 with DA- and MS-detector, XBridge C18_4.6×30 mm, 3.5 μm(Waters), 60° C.

% Sol % Time [min] [H₂O 0.1% NH₄OH] Sol [Acetonitrile] Flow [ml/min] 0.095.0 5.0 4.0 0.15 95.0 5.0 4.0 1.5 0.0 100.0 4.0 1.85 0.0 100.0 4.0HPLC-V:

Sunfire C18_3.0×30 mm, 2.5 μm (Waters), 60° C.

% Sol Time [min] % Sol [H₂O 0.1% TFA] [Acetonitrile] Flow [ml/min] 0.098.0 2.0 2.0 1.2 0.0 100.0 2.0 1.4 0.0 100.0 2.0HPLC-W:

Sunfire C18_3.0×30 mm, 2.5 μm (Waters), 60° C.

% Sol Time [min] % Sol [H₂O 0.1% TFA] [Acetonitrile] Flow [ml/min] 0.099.0 1.0 2.0 0.9 0.0 100.0 2.0 1.1 0.0 100.0 2.0HPLC-X:

Waters Acquity with DA- and MS-detector and CTC autosampler, SunfireC18_2.1×30 mm, 2.5 μm (Waters), 60° C.

% Sol Time [min] % Sol [H₂O 0.1% TFA] [Acetonitrile] Flow [ml/min] 0.099.0 1.0 1.5 0.02 99.0 1.0 1.5 1.0 0.0 100.0 1.5 1.1 0.0 100.0 1.5HPLC-Y:

Waters Acquity with 3100 MS, Sunfire C18_3.0×30 mm, 2.5 μm (Waters), 60°C.

% Sol [H2O 0.1% % Sol [Acetonitrile Time [min] TFA] 0.08% TFA] Flow[ml/min] 0.0 95.0 5.0 1.5 1.3 0.0 100.0 1.5 1.5 0.0 100.0 1.5 1.6 95.05.0 1.5Preparation of Intermediates:

Intermediate I.1: 2-amino-4-bromo-6-fluoro-benzonitrile

5.0 g (22.9 mmol) 4-bromo-2,6-difluorobenzonitrile are dissolved in 200ml of a solution of NH₃ in ethanol and heated in a pressure vessel to90° C. for 20 h. After cooling to RT the solvent is evaporated and theresidual taken in up in water/DCM. The organic phase is separated, driedand evaporated.

Yield: 4.9 g (99%), ESI-MS: m/z=213/215 (M−H)⁻, R_(t)(HPLC): 1.72 min(HPLC-R)

Intermediate II.1:N′-(5-bromo-2-cyano-3-fluoro-phenyl)-N,N-dimethyl-formamidine

A mixture of 17.0 g (79.1 mmol) 2-amino-4-bromo-6-fluoro-benzonitrileand 140 ml of N,N-dimethylformamide dimethyl acetal is heated to 120° C.for 2 h. After cooling RT the solvent is evaporated and the residualtaken up in diethyl ether, filtered and dried. Yield: 20.5 g (96%),ESI-MS: m/z=270/272 (M+H)⁺, R_(t)(HPLC): 0.83 min (HPLC-H)

The following Intermediates are prepared in a similar manner tointermediate II.1 from the corresponding anilines which are commerciallyavailable or can be obtained according to (a) U.S. Pat. No. 3,987,192 A1and (b) J. Med. Chem. 1981, 24 (6), 742.

ESI-MS m/z Int# Structure Starting Material M + H+ R_(t)(HPLC) II.2

2-amino-4-bromo- 6-methyl- benzonitrile^((a)) 266/268 0.57 min (HPLC-A)II.3

2-amino-6-chloro- benzonitrile^((b)) 208 0.47 min (HPLC-A) II.4

2-amino-6-bromo- benzonitrile^((b)) 252/254 0.53 min (HPLC-A)

Intermediate II.5:N′-[3-bromo-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

A mixture of 0.2 g (0.96 mmol) intermediate II.3, 0.2 g (0.67 mmol)Bis(pinacolato)diborane, 26 mg (0.01 mmol)4,4′-Di-tert-butyl-[2,2]bipyridinyl and 40 mg (0.06 mmol)chloro(1,5-cyclooctadiene)iridium(I) dimer is heated in heptane atreflux for 2 days. After cooling to RT the solvent is evaporated and theresidual taken in up in water/EtOAc. The organic phase is separated,dried and evaporated yielding the crude corresponding boronic acidderivative which is dissolved in MeOH. 0.1 g (0.75 mmol)dimethylsulfoximine and 14 mg (0.08 mmol) Copper(II) acetate are addedand the reaction mixture stirred at RT over night. After addition ofMeOH and concentrated NH₃ solution, the solvent is evaporated and theresidual purified by FC.

Yield: 0.1 g (58%), ESI-MS: m/z=299 (M+H)⁺, R_(t)(HPLC): 0.68 min(HPLC-M)

Intermediate II.6:N′-[3-bromo-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

A mixture of 2.0 g (9.63 mmol) intermediate II.3, 1.7 g (6.72 mmol)Bis(pinacolato)diborane, 21 mg (0.08 mmol)4,4′-Di-tert-butyl-[2,2]bipyridinyl and 16 mg (0.02 mmol)chloro(1,5-cyclooctadiene)iridium(I) dimer and THF is heated in apressure vessel to 80° C. for 21 h. Additional 0.2 g (0.79 mmol)Bis(pinacolato)diborane, 4′-Di-tert-butyl-[2,2]bipyridinyl andchloro(1,5-cyclooctadiene)iridium(I) dimer are added and heating iscontinued over night. After cooling to RT the solvent is evaporated andthe residual is treated with cyclohexane, filtered and washed withcyclohexane giving rise to 2.3 g of the crude boronic acid derivative.

To 2.3 g (4.8 mmol) of the crude boronic acid derivative, 3.0 g (13.4mmol) CuBr₂ methanol and water are added and the mixture is heated in apressure vessel to 80° C. for 4 h. The reaction mixture is concentratedand DCM added. The organic phase is separated, washed with brine, driedand evaporated and the residual purified by FC giving rise to 0.9 g2-Amino-4-bromo-6-chloro-benzonitrile which was converted to theformamidine derivative in similar manner as intermediate II.1.

ESI-MS: m/z=286 (M+H)⁺, R_(t)(HPLC): 0.85 min (HPLC-A)

Intermediate II.7:N′-[3-bromo-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

Was prepared in a similar manner as intermediate II.5 from intermediateII.4. ESI-MS: m/z=343/345 (M+H)⁺, R_(t)(HPLC): 0.66 min (HPLC-E)

Intermediate II.8:N′-(5-bromo-2-cyano-3-methoxy-phenyl)-N,N-dimethyl-formamidine

A mixture of 3.0 g (11.1 mmol) intermediate II.1, 17.4 g MeOH (555.4mmol), 4.3 g (13.3 mmol) Cs₂CO₃ and 50 ml dioxane was heated in apressure vessel for 5 h to reflux. After cooling to RT the solvent wasevaporated and the residual purified by FC (DCM). Yield: 2.4 g (75%),ESI-MS: m/z=282/284 (M+H)⁺, R_(t)(HPLC): 0.97 min (HPLC-D)

Intermediate II.9:N′-[2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-3-methyl-phenyl]-N,N-dimethyl-formamidine

To a solution of 0.5 g (1.9 mmol) intermediate II.2 in 20 ml dioxane 0.2g (2.3 mmol) dimethylsulphoximine, 0.1 g (0.4 mmol)2-(di-t-butylphosphino) biphenyl, 0.1 g (0.14 mmol) Pd₂dba₃ and 0.3 g(2.7 mmol) sodium tert-butoxide were added and the mixture heated to 80°C. for 1 h. The reaction mixture was diluted with water and acidifiedwith citric acid and extracted with EtOAc, then basified and extractedwith DCM. The organic phases were pooled dried and evaporated.

Yield: 0.4 g (83%), ESI-MS: m/z=279 (M+H)⁺, R_(t)(HPLC): 0.59 min(HPLC-F)

Intermediate II.10:N′-[2-cyano-3-cyclopropyl-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

To a solution of 100 mg (0.29 mmol) intermediate II.7 in 20 ml dioxane25 mg (0.29 mmol) cyclopropylboronic acid, 0.1 g (0.4 mmol)1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II), 121 mg (2.7mmol) potassium carbonate were added and the mixture heated to 80° C.over night. The reaction mixture was cooled to RT and diluted with MeOHand evaporated. The residual was purified by HPLC.

Yield: 70 mg (79%), ESI-MS: m/z=305 (M+H)⁺, R_(t)(HPLC): 0.68 min(HPLC-A)

Intermediate II.11:N′-[2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-3-(trifluoromethyl)phenyl]-N,N-dimethyl-formamidine

Was prepared in a similar manner as intermediate II.5 via 11.3 from2-amino-6-(trifluoromethyl)benzonitrile.

ESI-MS: m/z=242 (M+H)⁺, R_(t)(HPLC): 0.71 min (HPLC-E)

Intermediate II.12:N′-[2-cyano-5-[(1-oxothiolan-1-ylidene)amino]-3-(trifluoromethyl)phenyl]-N,N-dimethyl-formamidine

Was prepared in a similar manner as intermediate II.5 via 11.3 from2-amino-6-(trifluoromethyl)benzonitrile.

ESI-MS: m/z=359 (M+H)⁺, R_(t)(HPLC): 0.77 min (HPLC-E)

Intermediate II.13:N′-[2-cyano-3-methyl-5-[(4-oxo-1,4-oxathian-4-ylidene)amino]phenyl]-N,N-dimethyl-formamidine

Was prepared in a similar manner as intermediate II.5 via 11.3 from2-amino-6-(trifluoromethyl)benzonitrile.

ESI-MS: m/z=375 (M+H)⁺, R_(t)(HPLC): 0.75 min (HPLC-E)

Intermediate II.14: tert-butyl1-[4-cyano-3-[dimethylaminomethyleneamino]-5-methyl-phenyl]imino-1-oxo-1,4-thiazinane-4-carboxylate

Was prepared in a similar manner as intermediate II.5 via 11.3 from2-amino-6-(trifluoromethyl)benzonitrile.

ESI-MS: m/z=474 (M+H)⁺, R_(t)(HPLC): 0.91 min (HPLC-E)

Intermediate II.15:N′-[3-flouro-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

Was prepared in a similar manner as intermediate II.9 from intermediateII.1.

ESI-MS: m/z=283 (M+H)⁺, R_(t)(HPLC): 0.58 min (HPLC-B)

Intermediate II.16: N′-[3-chloro-2-cyano-5-[(ethyl-methyl-oxoλ⁶-sulfanylidene)amino]phenyl]-N,N-dimethyl-formamidine

Was prepared in a similar manner as intermediate II.5 from intermediateII.3.

ESI-MS: m/z=313 (M+H)⁺, R_(t)(HPLC): 0.35 min (HPLC-G)

Intermediate II.17:N′-[3-flouro-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

Was prepared in a similar manner as intermediate II.9 from intermediateII.2.

ESI-MS: m/z=305 (M+H)⁺, R_(t)(HPLC): 0.63 min (HPLC-B)

Intermediate II.18N′-(3-chloro-2-cyano-5-iodo-phenyl)-N,N-dimethyl-formamidine

A mixture of 4.0 g (19.3 mmol) intermediate II.3, 5.4 g (21.2 mmol)bis(pinacolato)diborane, 60 mg (0.22 mmol)4,4′-di-tert-butyl-[2,2]bipyridinyl and 50 mg (0.08 mmol)methoxy(1,5-cyclooctadiene)iridium(I) dimer and heptane is heated in apressure vessel to 110° C. over night. After cooling to RT theprecipitate is filtered off and dried giving rise to 5.5 g of the crudeboronic acid derivative.

To 1.6 g (4.8 mmol) of the crude boronic acid derivative, 0.1 g (0.6mmol) CuI, 1.2 g (7.2 mmol) KI, methanol and water are added and themixture is heated in a pressure vessel to 90° C. over night. Thereaction mixture is cooled to RT and EtOAc is added. The organic phaseis separated, dried and evaporated and the residual purified by FC.

ESI-MS: m/z=334 (M+H)⁺, R_(t)(HPLC): 0.80 min (HPLC-A)

Intermediate III.1: 4-Fluoro-2-(2-fluoro-1-methyl-ethoxy)-phenylamine

0.29 g (3.77 mmol) 1-fluoro-propan-2-ol in 20 mL THF is cooled down to0° C. 4.90 mL (1M in THF; 4.90 mmol) LiHMDS is added drop wise. After 60minutes of stirring at 0° C. 0.60 g (3.77 mmol)2,4-difluoro-1-nitro-benzene is added. The mixture is stirred for 2 h.The mixture is diluted with water and EtOAc. The organic layer is washedwith brine, separated, dried and evaporated giving rise to the crude4-fluoro-2-(2-fluoro-1-methyl-ethoxy)-1-nitro-benzene. 80.0 mg palladiumon charcoal (10%) and MeOH are added hydrogenated in a Parr apparatus(RT; 50 psi; 5 h). The catalyst is filtered off and the solvent isevaporated.

Yield: 0.60 g (87%), ESI-MS: m/z=188 (M+H)⁺, R_(t)(HPLC): 0.60 min(HPLC-E)

Intermediate III.2: 2-(1-ethoxy-2,2,2-trifluoro-ethoxy)-4-fluoro-aniline

Was prepared in a similar manner as intermediate III.1 from2,4-difluoro-1-nitro-benzene and 1-ethoxy-2,2,2-trifluoro-ethanol.

ESI-MS: m/z=254 (M+H)⁺, R_(t)(HPLC): 0.93 min (HPLC-E)

Intermediate III.3: 2-(1-ethoxy-2,2,2-trifluoro-ethoxy)pyridin-3-amine

Was prepared in a similar manner as intermediate III.1 from2-chloropyridin-3-amine and 1-ethoxy-2,2,2-trifluoro-ethanol.

ESI-MS: m/z=237 (M+H)⁺, R_(t)(HPLC): 0.98 min (HPLC-E)

Intermediate III.4:4-Fluoro-2-[1-(3-methyl-isoxazol-5-yl)ethoxy]-phenylamine

To a solution of 4.15 g (32.64 mmol) 1-(3-Methylisoxazol-5-yl)ethanol inTHF 32.64 mL (1M in THF; 32.64 mmol) LiHMDS is added drop wise. After 30minutes of stirring 5.19 g (32.64 mmol) 2,4-difluoro-1-nitro-benzene isadded. The mixture is stirred over night. The mixture is diluted withwater and EtOAc. The organic layer is separated, washed with water,dried and evaporated. The residue is purified by FC giving rise to5-[1-(5-fluoro-2-nitro-phenoxy)ethyl]-3-methyl-isoxazole.

6.61 g (24.84 mmol)5-[1-(5-fluoro-2-nitro-phenoxy)ethyl]-3-methyl-isoxazole and 24.66 g(109.30 mmol) tin(II)chloride dihydrate in EtOAc are stirred for 1 h atreflux. The mixture is diluted with 180 mL EtOAc and 180 mL aq. NaOH(4M). The organic layer is separated and the aqueous layer is extractedwith EtOAc. The combined organic layers are washed with water and brine,separated, dried and evaporated. The residue is purified by FC.

Yield: 4.90 g (84%), ESI-MS: m/z=237 (M+H)⁺

Intermediate III.5:4-fluoro-2-[(1R)-1-(3-methylisoxazol-5-yl)ethoxy]aniline

To a mixture of 1.0 g (16.9 mmol) acetaldehyde oxime, 1.19 g (16.9 mmol)(R)-(+)-3-butyl-2-ol, 0.18 g (1.72 mmol) triethylamine and DCM are addeddropwise 21.4 ml (28.78 mmol) of 10% sodium hypochlorite in water. Thereaction mixture is stirred for 1 h and the evaporated and purified byFC (DCM/MeOH 9:1) giving rise to (1R)-1-(3-methylisoxazol-5-yl)ethanol.

Yield: 0.7 g (33%), ESI-MS: m/z=128 (M+H)⁺, R_(t)(HPLC): 0.28 min(HPLC-G) III.5 was prepared in a similar manner as the racemateintermediate III.4 from 2,4-difluoro-1-nitro-benzene and(1R)-1-(3-methylisoxazol-5-yl)ethanol.

ESI-MS: m/z=237 (M+H)⁺

Intermediate III.6:2-[(1R)-1-(3-methylisoxazol-5-yl)ethoxyl]pyridin-3-amine

To a solution of 0.3 g (2.44 mmol)1(1R)-1-(3-methylisoxazol-5-yl)ethanol in THF 2.45 mL (1M in THF; 2.45mmol) LiHMDS is added drop wise. After 30 minutes of stirring 0.3 g(2.04 mmol) 2-fluoro-3-nitro-pyridine is added. The mixture is stirredover night. The mixture is diluted with 1 N HCl and water andneutralized with NH₃. EtOAc is added and the organic layer is separated,washed with brine, dried and evaporated to furnish3-methyl-5-[(1R)-1-[(3-nitro-2-pyridyl)oxy]ethyl]isoxazole.

A mixture of 0.5 g (2.09 mmol)3-methyl-5-[(1R)-1-[(3-nitro-2-pyridyl)oxy]ethyl]isoxazole and acetoneare cooled to 5° C. and 87 ml (17.4 mmol) of titanium(III)chloride 20%in water and 24 ml (96 mmol) of a 4M solution of NH₄Cl in water areadded. The mixture is warmed to RT and stirred over night diluted withEtOAc and water. The organic layer is separated and the aqueous layer isextracted with EtOAc. The combined organic layers are washed with brine,dried and evaporated. The residue is purified by FC (DCM/MeOH 95:5).

Yield: 0.3 g (72%), ESI-MS: m/z=220 (M+H)⁺, R_(t)(HPLC): 0.41 min(HPLC-G)

Intermediate III.7:(2R)-2-[(3-amino-2-pyridyl)oxy]-N-(2,2,2-trifluoroethyl)propanamide

To a solution of 5.3 g (50.5 mmol) (R)-2-Hydroxy-propionic acid methylester in THF 50.5 mL (1M in THF; 50.5 mmol) LiHMDS is added drop wise.After 10 minutes of stirring 4.0 g (25.2 mmol) 2-choro-3-nitro-pyridineis added. The mixture is stirred at 60° C. over night. The solvent isevaporated and the residue take up EtOAc washed with water, dried andevaporated to give rise to methyl(2R)-2-[(3-nitro-2-pyridyl)oxy]propanoate A mixture of 3.0 g (13.3 mmol)of methyl (2R)-2-[(3-nitro-2-pyridyl)oxy]propanoate and 5.0 ml 4 mol/laq. NaOH solution in methanol are stirred at RT for 30 min. 5.0 ml 4mol/l aq. HCl are added and the reaction mixture concentrated. Theprecipitate is filtered off, dissolved in DCM, dried and evaporatedyielding (2R)-2-[(3-nitro-2-pyridyl)oxy]propanoic acid.

A mixture of 500 mg (2.4 mmol) (2R)-2-[(3-nitro-2-pyridyl)oxy]propanoicacid 320 mg (2.4 mmol) 2,2,2-Trifluoro-ethylamine hydrochloride, 896 mg(2.4 mmol) HATU and 1210 μl (7.0 mmol) N,N-Diisopropylethylamine in DMFstirred at RT over night. The solvent is evaporated. The residual isdissolved in DCM, dried, evaporated and purified by FC yielding(2R)-2-[(3-nitro-2-pyridyl)oxy]-N-(2,2,2-trifluoroethyl)propanamide.

To 500 mg (1.7 mmol)(2R)-2-[(3-nitro-2-pyridyl)oxy]-N-(2,2,2-trifluoroethyl)propanamide 100mg Raney-Nickel and MeOH are added and the mixture is hydrogenated in aParr apparatus (RT; 3 bar; over night). The catalyst is filtered off andthe solvent is evaporated.

Yield: 440 mg (98%), ESI-MS: m/z=264 (M+H)⁺

Intermediate III.8:4-fluoro-2-[2,2,2-trifluoro-1-(3-methylisoxazol-5-yl)ethoxy]aniline

A mixture of 0.1 g (0.9 mmol) 3-Methyl-isoxazole-5-carbaldehyde and 14mg (0.09 mmol) CsF and THF is cooled to −5° C. 540 μl (1.1 mmol)trimethyl(trifluormethyl)-silane 2 M in THF is added dropwise and after30 min the mixture is allowed to reach RT. After cooling with ice andaddition of 5 ml 1 N aq. HCl, the mixture is stirred at RT over night,diluted with water and extracted with DCM. The combined organic layersare dried and evaporated giving rise to2,2,2-trifluoro-1-(3-methylisoxazol-5-yl)ethanol. Intermediate III.8 isprepared in a similar manner as intermediate III.4 from2,4-difluoro-1-nitro-benzene and2,2,2-trifluoro-1-(3-methylisoxazol-5-yl)ethanol.

ESI-MS: m/z=291 (M+H)⁺, R_(t)(HPLC): 0.90 min (HPLC-E)

Intermediate III.9: 3-(2-amino-5-fluoro-phenoxy)-2-methyl-butan-2-ol

Is prepared in a similar manner as intermediate III.1 from2,4-difluoro-1-nitro-benzene and 2-methylbutane-2,3-diol.

ESI-MS: m/z=254 (M+H)⁺

Intermediate III.10:3-(2-amino-5-fluoro-phenoxy)-2,2-dimethyl-butanenitrile

Is prepared in a similar manner as intermediate III.1 from2,4-difluoro-1-nitro-benzene and 3-hydroxy-2,2-dimethyl-butanenitrile.

ESI-MS: m/z=223 (M+H)⁺

Intermediate III.11:4-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]aniline

Is prepared in a similar manner as intermediate III.1 from2,4-difluoro-1-nitro-benzene and (2R)-1,1,1-trifluoropropan-2-ol.

ESI-MS: m/z=224 (M+H)⁺, R_(t)(HPLC): 0.77 min (HPLC-B)

Intermediate III.12:4-amino-3-(2,2,2-trifluoro-1-methyl-ethoxy)benzonitrile

Is prepared in a similar manner as intermediate III.4 from3-fluoro-4-nitro-benzonitrile and 1,1,1-trifluoro-propan-2-ol.

ESI-MS: m/z=231 (M+H)⁺, R_(t)(HPLC): 0.95 min (HPLC-E)

Intermediate III.13:4-amino-3-[1-(3-methylisoxazol-5-yl)ethoxy]benzamide

Is prepared in a similar manner as intermediate III.4 from3-fluoro-4-nitro-benzamide and 1-(3-methylisoxazol-5-yl)ethanol.

ESI-MS: m/z=262 (M+H)⁺, R_(t)(HPLC): 0.35 min (HPLC-G)

Intermediate III.14:(2R)-2-(2-amino-5-fluoro-phenoxy)-3-fluoro-propan-1-ol

Is prepared in a similar manner as intermediate III.1 from2,4-difluoro-1-nitro-benzene and (2R)-1-benzyloxy-3-fluoro-propan-2-ol.

ESI-MS: m/z=204 (M+H)⁺

Intermediate III.15:(2R)-2-(2-amino-5-fluoro-phenoxy)-3,3,3-trifluoro-propan-1-ol

Is prepared in a similar manner as intermediate III.1 from2,4-difluoro-1-nitro-benzene and(2R)-3-benzyloxy-1,1,1-trifluoro-propan-2-ol.

ESI-MS: m/z=240 (M+H)⁺

Intermediate III.16:(2R)-2-(2-amino-5-fluoro-phenoxy)-N-(2,2,2-trifluoroethyl)propanamide

Is prepared in a similar manner as intermediate III.7 from2,4-difluoro-1-nitro-benzene.

ESI-MS: m/z=281 (M+H)⁺, R_(t)(HPLC): 0.67 min (HPLC-A)

Intermediate III.17:(2R)-2-[(3-amino-2-pyridyl)oxy]-N-(2,2-difluoroethyl)propanamide

Is prepared in a similar manner as intermediate III.7 from2-choro-3-nitro-pyridine and 2,2-difluoroethanamine.

ESI-MS: m/z=246 (M+H)⁺

Intermediate III.18:(2R)-2-(2-amino-5-fluoro-phenoxy)-N-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]propanamide

Is prepared in a similar manner as intermediate III.7 from2,4-difluoro-1-nitro-benzene and 1,1,1,3,3,3-hexafluoropropan-2-amine.

ESI-MS: m/z=349 (M+H)⁺, R_(t)(HPLC): 0.97 min (HPLC-B)

The following Intermediates are prepared according to the givenreferences, if no reference is given the intermediate is commerciallyavailable:

Name Structure Reference III.50

WO2011/104338 III.51

III.52

WO2011/212103 III.53

WO2010/23181 III.54

U.S. Pat. No. 5,750,471 III.55

III.56

The following Intermediates are prepared according to the givenreferences:

Name Structure Reference IV.1

WO 2008/141843 IV.2

WO 2008/141843 IV.3

WO2008/141843 IV.4

Adaptation of WO2011/29537 IV.5

WO 2008/141843 IV.6

Adaptation of WO 2008/141843 V.7

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.8

Org. Lett., 2004, 6(8), 1305-1307 V.9

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.10

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.11

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.12

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.13

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.14

Adaptation of Org. Lett., 2004, 6(8), 1305-1307. Isomer 1: R_(t): 0.64min (HPLC-B) V.15

Adaptation of Org. Lett., 2004, 6(8), 1305-1307. Isomer 2: R_(t): 0.58min (HPLC-Y) V.16

Adaptation of Org. Lett., 2004, 6(8), 1305-1307. EI-MS: m/z = 134 (M +H)⁺, mp: 48-50° C. V.17

Adaptation of Org. Lett., 2004, 6(8), 1305-1307. EI-MS: m/z = 148 (M +H)⁺, mp: 135-139° C. V.18

Adaptation of Org. Lett., 2004, 6(8), 1305-1307. EI-MS: m/z = 281 (M +H)⁺, R_(t): 0.74 min (HPLC-A) V.19

Side product in the last step of the sythesis of V.18. EI-MS: m/z = 205(M + H)⁺

Intermediate V.1:2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenol

6.7 g (25 mmol) of 11.2 and 5.7 g (26 mmol) of IV.60 is dissolved inacetic acid and heated to 100° C. for 1 h. After cooling to RT thereaction mixture is diluted with water and the precipitate is filteredoff and washed with water. The crude product is treated with 80 mlethanol, filtered and dried yieldingN-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine.

Yield: 7.1 g (65%), ESI-MS: m/z=438 (M+H)⁺, R_(t)(HPLC): 1.12 min(HPLC-M) 3.1 g (7 mmol) ofN-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine, 0.8g (8.8 mmol) dimethylsulphoximine (IV.1), 0.4 g (1.4 mmol)2-(di-t-butylphosphino) biphenyl, 0.5 g (0.5 mmol) Pd₂dba₃ and 1.0 g(10.2 mmol) sodium tert-butoxide in dioxane are heated to 80° C. for 4.5h. After cooling to RT the reaction mixture is filtered, diluted withwater and extracted with EtOAc. The organic layers are pooled, dried andevaporated. The residue is purified by FC giving rise toN-(2-benzyloxy-4-fluoro-phenyl)-7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-amine.

Yield: 2.8 g (88%), ESI-MS: m/z=451 (M+H)+

To 0.5 g (1.1 mmol) ofN-(2-benzyloxy-4-fluoro-phenyl)-7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-amineare added 50 mg palladium on charcoal (10%) and MeOH and THF and mixtureis hydrogenated in a Parr apparatus (RT; 3 bar; 3 h). DMF and Ethanolare added and mixture heated to 70° C., the catalyst is filtered off andthe solvent is evaporated.

Yield: 0.33 g (83%), ESI-MS: m/z=361 (M+H)⁺, R_(t)(HPLC): 0.75 in(HPLC-E)

Intermediate V.2:5-fluoro-2-[[5-methyl-7-[(1-oxothiolan-1-ylidene)amino]quinazolin-4-yl]amino]phenol

Is prepared in a similar manner as intermediate V.1 using II.2, III.54and IV.5.

ESI-MS: m/z=387 (M+H)⁺, R_(t)(HPLC): 0.56 min (HPLC-M)

Intermediate V.3:2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-fluoro-quinazolin-4-yl]amino]-5-fluoro-phenol

Is prepared in a similar manner as intermediate V.1 using II.1, III.54and IV.1.

ESI-MS: m/z=365 (M+H)⁺, R_(t)(HPLC): 1.13 min (HPLC-F)

Intermediate V.4:5-fluoro-2-[[5-fluoro-7-[(1-oxothiolan-1-ylidene)amino]quinazolin-4-yl]amino]phenol

Is prepared in a similar manner as intermediate V.1 using II.1, III.54and IV.5.

ESI-MS: m/z=391 (M+H)⁺, R_(t)(HPLC): 1.11 min (HPLC-F)

Intermediate V.5:2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methoxy-quinazolin-4-yl]amino]-5-fluoro-phenol

Is prepared in a similar manner as intermediate V.1 using II.8, III.54and IV.1.

ESI-MS: m/z=377 (M+H)⁺, R_(t)(HPLC): 1.13 min (HPLC-F)

Intermediate V.6:5-fluoro-2-[[5-methoxy-7-[(1-oxothiolan-1-ylidene)amino]quinazolin-4-yl]amino]phenol

Is prepared in a similar manner as intermediate V.1 using II.8, III.54and IV.5.

ESI-MS: m/z=403 (M+H)⁺, R_(t)(HPLC): 1.12 min (HPLC-F)

Intermediate V.9:5-fluoro-2-[[5-methyl-7-[(1-oxothietan-1-ylidene)amino]quinazolin-4-yl]amino]phenol

A mixture of 10 g (22.8 mmol) ofN-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine(Intermediate V.1 step 1) and DCM is cooled to 0° C. and 34.2 ml (34.2mmol) 1M BBr₃ in DCM are added dropwise. After 6 h water is addedcarefully and the precipitate is filtered off, suspended in water andneutralized with 32% aq. ammonia solution. After 2 h the precipitate isfiltered off and dried furnishing2-[(7-bromo-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenol. 1.5 g (4.3mmol) 2-[(7-bromo-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenol, 0.45g (4.3 mmol) 1-iminothietane 1-oxide (IV.6), 0.26 g (0.86 mmol)2-(di-t-butylphosphino) biphenyl, 0.3 g (0.33 mmol) Pd₂dba₃ and 0.61 g(6.4 mmol) sodium tert-butoxide in dioxane are heated to 80° C. for 3 h.After cooling to RT the reaction mixture is filtered and evaporated. Theresidue is purified by FC.

ESI-MS: m/z=373 (M+H)⁺, R_(t)(HPLC): 0.79 min (HPLC-A)

Intermediate VI.1:(2R)-2-[2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenoxy]propanoicacid

A mixture of 0.4 g (0.9 mmol) of example 3.022 and 2.6 ml 1 mol/l aq.NaOH solution in ethanol:THF 1:1 are stirred over night. 2.6 ml 1 mol/laq. HCl are added and the precipitate is filtered off, washed with MeOHand dried.

Yield: 0.3 g (80%), ESI-MS: m/z=433 (M+H)⁺, R_(t)(HPLC): 0.64 min(HPLC-B)

Intermediate VI.2:(2R)-2-[5-fluoro-2-[[5-methyl-7-[(1-oxothiolan-1-ylidene)amino]quinazolin-4-yl]amino]phenoxy]propanoicacid

Is prepared in a similar manner as Intermediate from example 3.012

ESI-MS: m/z=459 (M+H)⁺, R_(t)(HPLC): 0.65 min (HPLC-B)

The following Intermediates are prepared in a similar manner tointermediate VI.1 from the corresponding starting materials

ESI-MS m/z HPLC R_(t) Name Structure M + H⁺ Method VI.3

449 0.63 HPLC-M VI.4

445 0.64 HPLC-M VI.5

453 0.66 HPLC-B VI.6

459 0.82 HPLC-E VI.7

487 0.85 HPLC-E VI.8

465 0.67 HPLC-M VI.9

461 0.66 HPLC-M VI.10

449 0.69 HPLC-M VI.11

491 0.68 HPLC-M VI.12

491 0.67 HPLC-M VI.13

481 0.69 HPLC-M VI.14

460 0.82 HPLC-E VI.15

461 VI.16

465 0.66 HPLC-M VI.17

477 0.67 HPLC-M

Intermediate VII.1:(2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]-N-(2,2,2-trifluoroethyl)propanamide

30 g (111 mmol) of 11.1 and 24.1 g (111 mmol) of IV.60 is dissolved inacetic acid and heated to 80° C. for 1 h. After cooling to RT thereaction mixture is diluted with water and the precipitate is filteredoff and washed with water and dried yieldingN-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-fluoro-quinazolin-4-amine.

Yield: 47 g (96%), ESI-MS: m/z=442 (M+H)⁺, R_(t)(HPLC): 1.15 min(HPLC-E)

A mixture of 47 g (106 mmol) ofN-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-fluoro-quinazolin-4-amine andDCM is cooled to 0° C. and 159.4 ml (159.4 mmol) 1M BBr3 in DCM areadded dropwise. After 3 h aq NaHCO₃ solution is added carefully and theprecipitate is filtered off, suspended in water and neutralized with 32%aq. ammonia solution. The precipitate is filtered off and driedfurnishing 2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenol.

Yield: 38 g, ESI-MS: m/z=352 (M+H)⁺, R_(t)(HPLC): 0.85 min (HPLC-E)

To a mixture of 28 g (79.5 mmol)2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenol, 9.4 g (79.5mmol) (S)-2-Hydroxy-propionic acid ethyl ester, 25.1 g (95.6 mmol) PPh₃and THF 22 g (95.4 mmol) di-tert-butyl azodicarboxylate are added andthe mixture stirred over night. The solvent is evaporated andisopropanol is added, the precipitate is filtered off and driedfurnishing ethyl(2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoate.

Yield: 34 g (95%), ESI-MS: m/z=452 (M+H)⁺, R_(t)(HPLC): 1.09 min(HPLC-E)

A mixture of 34 g (75 mmol) of ethyl(2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoateand 225.5 ml 1 mol/l aq. NaOH solution in THF are stirred for 2 h at RT.The solvent is evaporated and water is added. The mixture is neutralizedwith 1 mol/l aq. HCl and the precipitate is filtered off and driedyielding(2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoicacid.

Yield: 28.3 g (89%), ESI-MS: m/z=424 (M+H)⁺, R_(t)(HPLC): 0.90 min(HPLC-E)

To a mixture of 300 mg (0.78 mmol)(2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoicacid and DMF, 0.3 ml (1.8 mmol) DIPEA, 105 mg (0.89 mmol)2,2,2-trifluoro-ethylamine and 344 mg (0.9 mmol) HATU are added. Themixture is stirred at RT for 3 h, water is added and the precipitate isfiltered and dried.

Yield: 350 mg (98%), ESI-MS: m/z=505 (M+H)⁺, R_(t)(HPLC): 0.97 min(HPLC-E)

Intermediate VII.3:(2R)-2-[2-[(7-bromo-5-methoxy-quinazolin-4-yl)amino]-5-fluoro-phenoxy]-N-(2,2,2-trifluoroethyl)propanamide

A mixture of 1.2 g (2.4 mmol) intermediate VII.1 1.2 g (3.7 mmol) Cs₂CO₃and THF:MeOH 1:1 is heated to 70° C. for 4 h and over night at 50° C.The reaction mixture was evaporated and the residual washed withmethanol and water and dried.

Yield: 1.3 g, ESI-MS: m/z=519 (M+H)⁺, R_(t)(HPLC): 0.76 min (HPLC-B)

Intermediate VII.7:(2R)-2-[2-[(5-chloro-7-iodo-quinazolin-4-yl)amino]-5-fluoro-phenoxy]-N-(2,2,2-trifluoroethyl)propanamide

A mixture of 0.5 g (1.5 mmol) intermediate II.18 and formic acid isheated to 130° C. in a sealed tube, 1 ml 37% aq. HCl is added and themixture is heated to 130° C. for 24 h. After cooling to RT, water isadded and the precipitate is filtered off, washed with 5% aq. NaHCO₃solution and dried giving rise to 5-chloro-7-iodo-3H-quinazolin-4-one.

Yield: 0.4 g, ESI-MS: m/z=307 (M+H)⁺, R_(t)(HPLC): 0.71 min (HPLC-M) Toa mixture of 0.4 g (1.27 mmol) 5-chloro-7-iodo-3H-quinazolin-4-one, 0.5ml (3.18 mmol) DIPEA and toluene, 0.3 ml (2.8 mmol) POCl₃ is addeddropwise and stirred at RT for 1 h, the heated to 90° C. for 1.5 h.After cooling to RT the solvent is evaporated giving rise to crude4,5-dichloro-7-iodo-quinazoline.

To a mixture of the crude 4,5-dichloro-7-iodo-quinazoline and dioxane,0.4 g (1.27 mmol) intermediate III.16 is added and the mixture isstirred at RT for 2 h. The reaction mixture is diluted with water andneutralized with saturated aq. NaHCO₃ solution. The precipitate isfiltered off and dried.

Yield: 0.5 g, ESI-MS: m/z=569 (M+H)⁺, R_(t)(HPLC): 0.98 min (HPLC-A)

Intermediate VII.9:(2R)-2-[[3-[(7-bromo-5-methyl-quinazolin-4-yl)amino]-2-pyridyl]oxy]-N-(2,2-difluoroethyl)propanamide

673 mg (2.5 mmol) of 11.2 and 620 mg (2.5 mmol) of III.17 are dissolvedin acetic acid and heated to 80° C. for 1 h. After cooling to RT thereaction mixture is stirred over night and evaporated. The crude productis purified via HPLC.

Yield: 400 mg (34%), ESI-MS: m/z=466 (M+H)⁺

The following Intermediates are prepared in a similar manner tointermediate VII.1, VII.7 or VII.9 from the corresponding startingmaterials

ESI-MS m/z HPLC R_(t) Name Structure M + H⁺ Method VII.2

501 VII.4

462 0.77 HPLC-B VII.5

484 0.77 HPLC-X VII.6

569 1.17 HPLC-M VII.8

533 0.94 HPLC-BMethods of Preparation of Final CompoundsGeneral Procedure 1 (P1) for Examples Shown in Table 1 and Table 2:

Equimolar amounts of the respective intermediates II and III aredissolved in AcOH and heated to the given temperature for the giventime. The reaction mixture is evaporated and the residue is purified byHPLC.

The following examples in table 1 (example number given in column #) areprepared according to P1, details are given in the column synthesiscomment, the retention-time and mass (ESI-MS m/z M+H⁺) determined byHPLC-MS are given in the columns MS and RT.

TABLE 1 Synthesis # Structure SM MS RT Comment 1.001

II.9 III.12 464 0.7 min (HPLC-N) 75° C. 48 h 1.002

II.11 III.50 493 0.83 min (HPLC-I) 65° C. 4 h 1.003

II.5 III.11 477 0.93 min (HPLC-M) 65° C. 2 h 1.004

II.12 III.50 519 1.13 min (HPLC-P) 75° C. over night 1.005

II.16 III.6 487 0.78 min (HPLC-N) 95° C. 5 h 1.006

II.15 III.1 425 0.72 min (HPLC-B) 75° C. 4 h 1.007

II.15 III.52 444 0.9 min (HPLC-E) 75° C. over night 1.008

II.9 III.3 470 0.92 min (HPLC-E) 80° C. 4 h 1.009

II.14 III.50 534 0.7 min (HPLC-I) 65° C. 4 h 1.010

II.9 III.8 524 0.81 min (HPLC-I) 65° C. over night 1.011

II.17 III.50 465 0.82 min (HPLC-B) 65° C. over night 1.012

II.9 III.13 495 0.4 min (HPLC-G) 80° C. 24 h 1.013

II.9 III.51 457 1.06 min (HPLC-P) 80° C. 2 h; racemate 1.014

II.9 III.56 428 0.4 min (HPLC-G) 80° C. 24 h 1.015

II.9 III.1 421 0.72 min (HPLC-I) 80° C. 2 h 1.016

II.5 III.6 473 0.88 min (HPLC-M) 65° C. 3 h 1.017

II.9 III.52 440 0.89 min (HPLC-E) 80° C. over night 1.018

II.15 III.50 443 0.79 min (HPLC-B) 75° C. 4 h 1.019

II.5 III.5 490 0.42 min (HPLC-Q) 80° C. 3 h 1.020

II.15 III.51 461 0.85 min (HPLC-B) 75° C. 4 h 1.021

II.13 III.50 535 1.11 min (HPLC-P) 65° C. 4 h 1.022

II.10 III.50 465 0.68 min (HPLC-N) 65° C. over night 1.023

II.9 III.2 487 0.91 min (HPLC-E) 80° C. 4 hGeneral Procedure 2 (P2) for Examples Shown in Table 2:

1 eq of aryl bromide (if not described prepared according to P1) or aryliodide, 1.2 eq sulphoximine, 20 mol % 2-(di-tert-butylphosphino)biphenyl, 10 mol % Pd₂dba₃ and 1.4 eq sodium tert-butoxide are mixedwith dioxane and heated under an argon atmosphere to the giventemperature for the given time. The reaction mixture is concentrated andthe crude product purified by HPLC or FC.

The following examples in table 2 (example number given in column #) areprepared according to P2, details are given in the column synthesiscomment, the retention-time and mass (ESI-MS m/z M+H⁺) determined byHPLC-MS are given in the columns MS and RT.

TABLE 2 Synthesis # Structure SM MS RT Comment 2.001

II.2 III.9 473 1.3 min (HPLC-S) 90° C. 2 h 2.002

II.1 III.4 474 1.12 min (HPLC-J) 80° C. 2 h 2.003

II.2 III.9 447 1.25 min (HPLC-S) 90° C. 2 h 2.004

II.2 III.53 477 0.81 min (HPLC-A) 80° C. 4.5 h 2.005

II.2 III.54 454 0.81 min (HPLC-E) 80° C. 2 h; 2.006

II.2 III.11 469 0.55 min (HPLC-G) 80° C. 1 h 2.007

II.2 III.10 482 0.51 min (HPLC-G) 80° C. 2 h; 2.008

II.2 III.5 470 1.35 min (HPLC-O) 100° C. over night 2.009

II.2 III.6 479 0.55 min (HPLC-K) 80° C. 3 h 2.010

II.2 III.10 456 0.49 min (HPLC-G) 80° C. 2 h; 2.011

II.2 III.55 403 0.75 min (HPLC-A) 80° C. 2.5 h 2.012

II.2 III.5 496 1.37 min (HPLC-F) 100° C. over night 2.013

II.2 III.7 497 0.66 min (HPLC-B) 80° C. 4.5 h 2.014

II.6 III.5 516 0.55 min (HPLC-G) 80° C. 2.5 h 2.015

II.1 III.53 390 0.69 min (HPLC-C) 80° C. 2 h 2.016

II.2 III.5 511 0.44 min (HPLC-G) 2 h 80° C.; followed by deprotection inDCM with 11 eq TFA; over night 2.017

II.2 III.53 386 0.73 min (HPLC-A) 80° C. 2 h 2.018

II.2 III.6 453 0.51 min (HPLC-K) 80° C. 3 h 2.019

VII.2 555 0.35 min (HPLC-Q) 80° C. 3 h, followed by deprotection with 10eq TFA V.14 used absolute configuration n.D. 2.020

VII.2 555 0.67 min (HPLC-T) 80° C. 3 h, followed by deprotection with 10eq TFA V.15 used absolute configuration n.D. 2.021

VII.9 491 0.88 min (HPLC-M) 80° C. 4 h 2.022

VII.5 523 0.65 min (HPLC-N) 80° C. 6.5 h 2.023

VII.5 556 0.7 min (HPLC-T) 90° C. 4 h 2.024

VII.7 588 0.84 min (HPLC-A) 80° C. 1.5 h with Xantphos and Pd(OAc)₂2.025

VII.1 588 0.77 min (HPLC-T) 90° C. 3 h 2.026

VII.4 515 0.8 min (HPLC-A) 80° C. 1.5 h with Xantphos and Pd(OAc)₂ 2.028

VII.2 569 0.79 min (HPLC-E) 80° C. 3 h, followed by deprotection with 10eq TFA 2.029

VII.2 584 0.75 min (HPLC-T) 90° C. 3 h 2.030

VII.3 556 0.77 min (HPLC-T) 90° C. 3 h 2.031

VII.5 501 0.65 min (HPLC-B) 80° C. 4.5 h 2.032

VII.2 625 0.85 min (HPLC-A) 80° C. 1.5 h with Xantphos and Pd(OAc)₂2.033

VII.4 501 0.68 min (HPLC-T) 90° C. 3 h 2.034

VII.8 584 0.9 min (HPLC-T) 90° C. 2 h 2.035

VII.2 554 0.8 min (HPLC-T) 90° C. 3 h 2.036

II.2 III.14 449 0.5 min (HPLC-V) 80° C. 2 h 2.037

VII.7 574 0.88 min (HPLC-T) 80° C. 1.5 h with Xantphos and Pd(OAc)₂2.038

VII.2 568 0.82 min (HPLC-A) 80° C. 1.5 h with Xantphos and Pd(OAc)₂2.039

VII.5 509 0.64 min (HPLC-N) 80° C. 6.5 h 2.040

VII.1 560 0.85 min (HPLC-T) 90° C. 3 h 2.041

VII.6 594 0.9 min (HPLC-B) 80° C. 3 h 2.042

VII.2 540 0.76 min (HPLC-T) 90° C. 3 h 2.043

II.2 III.15 485 0.5 min (HPLC-G) 80° C. 2 h 2.044

VII.2 554 0.88 min (HPLC-A) 80° C. 1.5 h with Xantphos and Pd(OAc)₂2.045

VII.8 598 0.81 min (HPLC-T) 90° C. 2 h 2.046

VII.2 542 0.78 min (HPLC-T) 90° C. 3 h 2.047

VII.2 542 0.73 min (HPLC-B) 80° C. over night 2.048

II.2 III.11 483 0.90 min (HPLC-E) 90° C. over nightGeneral Procedure 3 (P3) for Examples Shown in Table 3:

To 1 eq of the corresponding phenol intermediate V, 2 eq of the alcoholand 3 eq of triphenyl phosphine in THF 3 eqdi-tert-butylazodicarboxylate are added and the reaction mixture isstirred at RT over night. The reaction mixture is concentrated andpurified by HPLC or FC.

General Procedure 4 (P4) for Examples Shown in Table 3:

To 1 eq of the corresponding phenol intermediate V, 2.5 eq of thealcohol in DMSO and 3 eq triphenyl phosphine and 3 eqdi-tert-butylazodicarboxylate are added. After stirring over night at RTthe same equivalents of triphenyl phosphine anddi-tert-butyldicarboxylate in dioxane are added. After stirring anothernight at RT the same equivalents of triphenyl phosphine anddi-tert-butyldicarboxylate in dioxane are added again. The reactionmixture is concentrated and purified by HPLC or FC.

To obtain the following examples (example number given in column #)shown in table 3, the corresponding compounds are prepared from theintermediate V and the respective alcohol according to P3 or P4. Detailsare given in the column synthesis comment, the retention-time and mass(ESI-MS m/z M+H⁺) determined by HPLC-MS are given in the columns MS andRT.

TABLE 3 Synthesis # Structure SM MS RT Comment 3.001

V.1 439 0.68 min (HPLC-B) P3 with 1,3- difluoropropan-2-ol 3.002

V.1 456 0.76 min (HPLC-K) P3 with 1-oxazol-2- ylethanol 3.003

V.1 460 0.71 min (HPLC-P) P4 with 5- (hydroxymethyl) oxazolidin-2-one3.004

V.1 469 0.58 min (HPLC-K) P3 with 1-imidazol- 1-ylpropan-2-ol 3.005

V.1 400 0.78 min (HPLC-P) P4 with 2- hydroxyacetonitrile 3.006

V.1 459 0.92 min (HPLC-P) P4 with tetrahydropyran-2- ylmethanol 3.007

V.1 466 0.6 min (HPLC-K) P3 with 1-(3- pyridyl)ethanol 3.008

V.1 451 0.84 min (HPLC-K) P3 with (2,2- difluorocyclopropyl) methanol3.009

V.1 456 0.86 min (HPLC-P) P4 with (5- methylisoxazol-3- yl)methanol3.010

V.1 459 0.83 min (HPLC-K) P3 with 1- tetrahydrofuran-2- ylethanol 3.011

V.6 556 1.26 min (HPLC-S) P3 with 1 eq. (2R)- 2-hydroxy-N-(2,2,2-trifluoroethyl) propanamide, DEAD and DCM as solvent 3.012

V.2 487 0.74 min (HPLC-B) P3 with (S)-2- Hydroxy-propionic acid ethylester 3.013

V.1 431 0.79 min (HPLC-P) P4 with 1-(oxetan-2- yl)propan-2-ol 3.014

V.1 454 0.86 min (HPLC-P) P4 with 1- (hydroxymethyl)cyclobutanecarbonitrile 3.015

V.1 483 0.65 min (HPLC-P) P4 with 1-(2- methylimidazol-1- yl)propan-2-ol3.016

V.1 413 0.89 min (HPLC-P) P4 with but-3-yn-2- ol 3.017

V.1 461 0.9 min (HPLC-P) P4 with methyl 2- hydroxybutanoate 3.018

V.1 418 0.55 min (HPLC-B) P3 followed by deprotection with 20% TFA inDCM with ((S)-2-Hydroxy- propyl)-carbamic acid tert-butyl ester 3.019

V.1 487 0.85 min (HPLC-K) P3 with 1- tetrahydropyran-4- ylpropan-2-ol3.020

V.1 459 0.79 min (HPLC-K) P3 with 1- tetrahydrofuran-3- ylethanol 3.021

V.1 466 0.77 min (HPLC-P) P4 with 1-(2- pyridyl)ethanol 3.022

V.1 461 0.72 min (HPLC-B) P3 with (S)-2- Hydroxy-propionic acid ethylester 3.023

V.1 469 0.76 min (HPLC-K) P3 with 1-(2- methylpyrazol-3- yl)ethanol3.024

V.2 418 0.55 min (HPLC-B) P3 followed by deprotection with 20% TFA inDCM with ((R)-2-Hydroxy- propyl)-carbamic acid tert-butyl ester 3.025

V.1 496 0.48 min (HPLC-N) P3 with N-(2- hydroxy-1-methyl- ethyl)methanesulfonamide 3.026

V.1 446 0.77 min (HPLC-P) P4 with 2-hydroxy- N,N-dimethyl- acetamide3.027

V.1 483 0.45 min (HPLC-Q) P3 with [1- (trifluoromethyl)cyclopropyl]methanol 3.028

V.1 489 0.86 min (HPLC-P) P4 with 1- tetrahydrofuran-3- yloxypropan-2-ol3.029

V.1 445 0.81 min (HPLC-P) P4 with (3- methyloxetan-3- yl)methanol 3.030

V.1 445 0.76 min (HPLC-P) P4 with propane- 1,3-diol 3.031

V.1 457 0.9 min (HPLC-P) P4 with 3,3,3- trifluoropropan-1-ol 3.032

V.1 461 0.84 min (HPLC-K) P3 with ethyl (2R)- 2- hydroxypropanoate 3.033

V.1 472 0.74 min (HPLC-P) P4 with 4- (hydroxymethyl) piperidin-2-one3.034

V.1 469 0.76 min (HPLC-K) P3 with 1-pyrazol-1- ylpropan-2-ol 3.035

V.1 472 0.78 min (HPLC-K) P3 with 1-thiazol-2- ylethanol 3.036

V.1 471 0.84 min (HPLC-P) P4 with 1-(3-methyl- 1,2,4-oxadiazol-5-yl)ethanol 3.037

V.1 458 0.72 min (HPLC-P) P4 with 4- (hydroxymethyl) pyrrolidin-2-one3.038

V.1 458 0.72 min (HPLC-P) P4 with (5R)-5- (hydroxymethyl)pyrrolidin-2-one 3.039

V.1 442 0.83 min (HPLC-P) P4 with isoxazol-3- ylmethanol 3.040

V.5 530 1.23 min (HPLC-S) P3 with 1 eq. (2R)- 2-hydroxy-N-(2,2,2-trifluoroethyl) propanamide, DEAD and DCM as solvent 3.041

V.1 471 0.78 min (HPLC-P) P4 with 1-(5-methyl- 1,3,4-oxadiazol-2-yl)ethanol 3.042

V.1 417 0.88 min (HPLC-K) P3 with butan-2-ol 3.043

V.1 458 0.72 min (HPLC-P) P4 with (5S)-5- (hydroxymethyl)pyrrolidin-2-one 3.044

V.1 461 0.74 min (HPLC-K) P3 with 1,4-dioxan- 2-ylmethanol 3.045

V.1 459 0.86 min (HPLC-P) P4 with tetrahydropyran-4- ylmethanol 3.046

V.1 466 0.65 min (HPLC-P) P4 with 1-(4- pyridyl)ethanol 3.047

V.4 544 1.82 min (HPLC-F) P3 with 1 eq. (2R)- 2-hydroxy-N-(2,2,2-trifluoroethyl) propanamide, DEAD and DCM as solvent 3.048

V.1 445 0.39 min (HPLC-Q) P3 with tetrahydrofuran-3- ylmethanol and DMSOas solvent 3.049

V.3 518 1.23 min (HPLC-F) P3 with 1 eq. (2R)- 2-hydroxy-N-(2,2,2-trifluoroethyl) propanamide, DEAD and DCM as solvent 3.050

V.1 433 0.8 min (HPLC-K) P3 with 1- methoxypropan-2-ol 3.051

V.1 528 0.75 min (HPLC-M) P4 with (2S)-2- hydroxy-N[(1R)-2,2,2-trifluoro-1- methyl- ethyl]propanamide 3.052

V.9 608 1.04 min (HPLC-M) P3 with (2S)-2- hydroxy-N,N- bis(2,2,2-trifluoroethyl) propanamide in Dioxane 3.053

V.1 560 0.95 min (HPLC-M) P3 with (2S)-N,N- bis(2,2- difluoroethyl)-2-hydroxy- propanamide 3.054

V.1 582 0.98 min (HPLC-M) P4 with (2S)-2- hydroxy-N-[2,2,2- trifluoro-1-(trifluoromethyl) ethyl]propanamide 3.055

V.1 596 0.8 min (HPLC-B) P4 with (2S)-2- hydroxy-N,N- bis(2,2,2-trifluoroethyl) propanamideGeneral Procedure 5 (P5) for Examples Shown in Table 4:

To 1 eq of the corresponding acid, 1.4 eq HATU and 2 eq TEA in DMF areadded. The corresponding amine is added and the mixture is stirred at RTfor 3 days. The reaction mixture is concentrated and purified by HPLC orFC.

General Procedure 6 (P6) for Examples Shown in Table 4:

To 1 eq of the corresponding acid, 1.1 eq TBTU and 2 eq TEA in DMF areadded. 1.0 eq of the corresponding amine is added and the mixture isstirred at RT over night. The reaction mixture is concentrated andpurified by HPLC or FC.

General Procedure 7 (P7) for Examples Shown in Table 4:

To 1 eq of the corresponding acid, 1.1 eq TBTU and 2 eq TEA in DMF areadded. 1.0 eq of the corresponding amine is added and the mixture isstirred at RT over night. The reaction mixture is concentrated. Someproducts are taken up in DMF/MeOH (9/1) and passed through Alox followedby elution with more solvent. The filtrate is evaporated and purified byHPLC or FC.

General Procedure 8 (P8) for Examples Shown in Table 4:

To 1 eq of the corresponding acid, 7.5 eq DIPEA 5 eq of thecorresponding amine in DMF are added. 1.5 eq HATU and the mixture isstirred at RT over night. The reaction mixture is concentrated andpurified by HPLC or FC.

General Procedure 9 (P9) for Examples Shown in Table 4:

To a mixture of 1 eq of the corresponding acid, 2 eq DIPEA and 5 eq ofthe corresponding amine in DMF are cooled to −65° C. and 2 eq1-propanephosphonic acid cyclic anhydride ca. 50% in DMF are added andthe mixture is slowly warmed to RT. The reaction mixture is concentratedand purified by HPLC or FC.

To obtain the following examples (example number given in column #)shown in table 4, the corresponding compounds are prepared from theacids and the respective amine according to P5, P6, P7, P8 or P9.Details are given in the column synthesis comment, the retention-timeand mass (ESI-MS m/z M+H⁺) determined by HPLC-MS are given in thecolumns MS and RT.

TABLE 4 # Structure SM MS RT Synthesis Comment 4.001

VI.1 542 0.82 min (HPLC-P) P6 with tetrahydrofuran-2- ylmethanamine4.002

VI.2 460 0.66 min (HPLC-B) P5 with 24 eq. dimethyl-amine 4.003

VI.1 514 0.92 min (HPLC-P) P6 with N- methylpropan-2- amine 4.004

VI.1 560 0.75 min (HPLC-P) P6 with 1,4- thiazinane 1-oxide 4.005

VI.2 502 0.62 min (HPLC-C) P7 with pyrrolidin-3-ol 4.006

VI.1 512 0.87 min (HPLC-P) P6 with pyrrolidine 4.007

VI.1 497 0.8 min (HPLC-P) P6 with 2- aminoacetonitrile 4.008

VI.1 516 0.75 min (HPLC-P) P6 with 1- aminopropan-2-ol 4.009

VI.2 488 0.33 min (HPLC-L) P5 with 1.8 eq. oxetane-3-amine 4.010

VI.1 528 0.76 min (HPLC-P) P6 with pyrrolidin-3-ol 4.011

VI.2 516 0.79 min (HPLC-P) P6 with tetrahydrofuran-2- ylmethanamine4.012

VI.2 536 0.96 min (HPLC-P) P6 with N-methyl-1- phenyl-methanamine 4.013

VI.2 502 0.94 min (HPLC-P) P6 with N,2- dimethylpropan-1- amine 4.014

VI.1 542 0.8 min (HPLC-P) P6 with tetrahydropyran-4- amine 4.015

VI.1 512 0.88 min (HPLC-P) P6 with cyclobutanamine 4.016

VI.2 486 0.84 min (HPLC-P) P6 with pyrrolidine 4.017

VI.1 562 1.1 min (HPLC-I) P6 with N-methyl-1- phenyl-methanamine 4.018

VI.2 470 0.79 min (HPLC-P) P6 with prop-2-yn-1- amine 4.019

VI.2 516 0.77 min (HPLC-P) P6 with tetrahydropyran-4- amine 4.020

VI.2 490 0.62 min (HPLC-C) P7 with 1- aminopropan-2-ol 4.021

VI.2 504 0.8 min (HPLC-P) P6 with 2- aminopropan-1-ol 4.022

VI.2 508 0.65 min (HPLC-B) P5 with 3 eq. dimethylsulfoximine; 1.1 eqTBTU used instead of HATU 4.023

VI.2 486 0.84 min (HPLC-P) P6 with cyclobutanamine 4.024

VI.1 543 0.8 min (HPLC-P) P6 with (1R,2S)-2- aminocyclopentanol 4.025

VI.1 514 0.92 min (HPLC-P) P6 with N- ethylethanamine 4.026

VI.1 540 0.99 min (HPLC-P) P6 with N- methylcyclopentana- mine 4.027

VI.1 496 0.82 min (HPLC-P) P6 with prop-2-yn-1- amine 4.028

VI.1 516 0.77 min (HPLC-P) P6 with 2- (methylamino)ethanol 4.029

VI.2 476 0.6 min (HPLC-C) P7 with 2- aminoethanol 4.030

VI.2 534 0.6 min (HPLC-C) P7 with 1,4- thiazinane 1-oxide 4.031

VI.2 488 0.89 min (HPLC-P) P6 with N- ethylethanamine 4.032

VI.2 502 0.72 min (HPLC-I) P5 with 1.5 eq. morpholine 4.033

VI.1 500 0.86 min (HPLC-P) P6 with propan-1- amine 4.034

VI.2 460 0.36 min (HPLC-L) P5 with 1.7 eq. ethylamine 4.035

VI.2 490 0.7 min (HPLC-I) P5 with 1.5 eq. 2- methoxy-ethylamine 4.036

VI.2 496 0.81 min (HPLC-P) P6 with 2,2- difluoroethanamine 4.037

VI.2 551 0.98 min (HPLC-P) P6 with N-methy1-2- phenyl-ethanamine 4.038

VI.2 516 0.76 min (HPLC-P) P6 with (1S,2S)-2- aminocyclopentanol 4.039

VI.2 471 0.77 min (HPLC-P) P6 with 2- aminoacetonitrile 4.040

VI.1 530 0.83 min (HPLC-P) P6 with 1- methoxypropan-2- amine 4.041

VI.1 530 0.87 min (HPLC-P) P6 with 2- (methylamino)ethanol 4.042

VI.1 500 0.85 min (HPLC-P) P6 with propan-2- amine 4.043

VI.1 522 0.84 min (HPLC-P) P6 with 2,2- difluoroethanamine 4.044

VI.1 510 0.86 min (HPLC-P) P6 with prop-2-yn-1- amine 4.045

VI.2 502 0.76 min (HPLC-P) P6 with (3S)- tetrahydrofuran-3- amine 4.046

VI.2 514 0.78 min (HPLC-P) P6 with piperidin-4- one 4.047

VI.1 458 0.74 min (HPLC-P) P6 with ammonia 4.048

VI.2 488 0.86 min (HPLC-P) P6 with butan-2- amine 4.049

VI.2 472 0.78 min (HPLC-P) P6 with azetidine 4.050

VI.1 514 0.89 min (HPLC-P) P6 with butan-2- amine 4.051

VI.1 486 0.83 min (HPLC-P) P6 with dimethyl- amine 4.052

VI.1 528 0.97 min (HPLC-P) P6 with N,2- dimethylpropan-1- amine 4.053

VI.2 514 0.96 min (HPLC-P) P6 with N- methylcyclopentana- mine 4.054

VI.1 540 0.81 min (HPLC-P) P6 with piperidin-4- one 4.055

VI.2 504 0.84 min (HPLC-P) P6 with 2-methoxy-N- methyl-ethanamine 4.056

VI.2 515 0.56 min (HPLC-B) P5 with 1.5 eq 1- methylpiperazine 4.057

VI.1 528 0.79 min (HPLC-P) P6 with (3S)- tetrahydrofuran-3- amine 4.058

VI.1 530 0.78 min (HPLC-P) P6 with 1-amino-2- methyl-propan-2-ol 4.059

VI.1 556 0.87 min (HPLC-P) P6 with 4- methoxypiperidine 4.060

VI.2 474 0.82 min (HPLC-P) P6 with propan-2- amine 4.061

VI.2 490 0.62 min (HPLC-C) P7 with 2- (methylamino)ethanol 4.062

VI.2 500 0.9 min (HPLC-P) P6 with piperidine 4.063

VI.1 577 1.01 min (HPLC-P) P6 with N-methyl-2- phenyl-ethanamine 4.064

VI.2 488 0.88 min (HPLC-P) P6 with N- methylpropan-2- amine 4.065

VI.2 516 0.78 min (HPLC-P) P6 with (1R,2S)-2- aminocyclopentanol 4.066

VI.2 484 0.83 min (HPLC-P) P6 with prop-2-yn-1- amine 4.067

VI.1 526 0.93 min (HPLC-P) P6 with piperidine 4.068

VI.2 474 0.77 min (HPLC-I) P5 with 1.5 eq. ethyl- methyl-amine 4.069

VI.2 504 0.75 min (HPLC-P) P6 with 1-amino-2- methyl-propan-2-ol 4.070

VI.1 498 0.82 min (HPLC-P) P6 with azetidine 4.071

VI.2 514 0.69 min (HPLC-B) P5 with 2.9 eq. 2,2,2- trifluoroethanamine4.072

VI.1 502 0.73 min (HPLC-P) P6 with 2- aminoethanol 4.073

VI.2 531 0.84 min (HPLC-P) P6 with 4- methoxypiperidine 4.074

VI.1 540 0.89 min (HPLC-P) P6 with 2,2,2- trifluoroethanamine 4.075

VI.1 542 0.79 min (HPLC-P) P6 with (1S,2S)-2- aminocyclopentanol 4.076

VI.5 494 0.4 min (HPLC-Q) P8 with propan-2- amine 4.077

VI.16 517 0.96 min (HPLC-M) P9 with (2S)-2- aminopropanenitrile 4.078

VI.5 498 0.37 min (HPLC-Q) P8 with 2- fluoroethanamine 4.079

VI.9 556 1.01 min (HPLC-M) P5 with 2 eq DIPEA and (2S)-1,1,1-trifluoropropan-2- amine 4.080

VI.5 516 0.38 min (HPLC-Q) P8 with 2,2- difluoroethanamine 4.081

VI.4 486 0.39 min (HPLC-Q) P8 with propan-2- amine 4.082

VI.4 510 0.77 min (HPLC-T) P5 with 2.5 eq HATU, 7 eq DIPEA andbicyclo[1.1.1]pentan- 3-amine 4.083

VI.2 514 0.49 min (HPLC-K) P5 with 7 eq DIPEA and 2,2,2-trifluoroethanamine 4.084

VI.6 541 0.75 min (HPLC-T) P5 with 2,2,2- trifluoroethanamine 4.085

VI.5 491 0.36 min (HPLC-Q) P8 with 2- aminoacetonitrile 4.086

VI.7 568 0.43 min (HPLC-Q) P5 with 2,2,2- trifluoroethanamine 4.087

VI.17 558 0.99 min (HPLC-M) P5 with 2,2,2- trifluoroethanamine 4.088

VI.10 544 0.43 min (HPLC-Q) P5 with 2 eq DIPEA and (2S)-1,1,1-trifluoropropan-2- amine 4.089

VI.4 540 0.41 min (HPLC-Q) P8 with 3,3,3- trifluoropropan-1- amine 4.090

VI.8 560 0.87 min (HPLC-B) P5 with(2R)-1,1,1- trifluoropropan-2- amine4.091

VI.5 534 0.41 min (HPLC-Q) P8 with 2,2,2- trifluoroethanamine 4.092

VI.10 530 0.69 min (HPLC-N) P5 with 2,2,2- trifluoroethanamine 4.093

VI.12 531 0.96 min (HPLC-M) P5 with 7 eq DIPEA and (2S)-2-aminopropanenitrile 4.094

VII.14 557 0.82 min (HPLC-T) P9 with (2S)-1,1,1- trifluoropropan-2-amine 4.095

VI.11 543 0.78 min (HPLC-T) P5 with 7 eq DIPEA and (2S)-2-aminopropanenitrile 4.096

VI.8 560 0.86 min (HPLC-B) P5 with (2S)-1,1,1- trifluoropropan-2- amine4.097

VI.3 487 0.35 min (HPLC-Q) P8 with 2- aminoacetonitrile 4.098

VI.15 556 0.86 min (HPLC-B) P5 with 1.2 eq DIPEA and (2S)-1,1,1-trifluoropropan-2- amine 4.099

VI.3 501 0.37 min (HPLC-Q) P8 with 2- aminopropanenitrile 4.100

VI.3 530 0.4 min (HPLC-Q) P8 with 2,2,2- trifluoroethanamine 4.101

VI.2 510 0.37 min (HPLC-Q) P5 with 7.3 eq DIPEA and 1,1-difluoropropan-2- amine 4.102

VI.13 533 0.94 min (HPLC-M) P9 with (2S)-2- aminopropanenitrile 4.103

VI.4 483 0.75 min (HPLC-M) P5 with 2- aminoacetonitrile 4.104

VI.4 540 0.84 min (HPLC-B) P5 with 2 eq DIPEA and (2S)-1,1,1-trifluoropropan-2- amine 4.105

VI.1 504 0.5 min (HPLC-W) P5 with 2.7 eq HATU, 11 eq DIPEA and 2-fluoroethanamine 4.106

VI.3 501 0.78 min (HPLC-B) P5 with 7.5 eq DIPEA and (2S)-2-aminopropanenitrile 4.107

VI.4 490 0.36 min (HPLC-Q) P8 with 2- fluoroethanamine 4.108

VI.3 544 0.4 min (HPLC-Q) P8 with 3,3,3- trifluoropropan-1- amine 4.109

VI.4 522 0.4 min (HPLC-Q) P8 with 1,1- difluoropropan-2- amine 4.110

VI.13 562 0.98 min (HPLC-M) P9 with 2,2,2- trifluoroethanamine 4.111

VI.9 524 0.96 min (HPLC-M) P5 with 2 eq DIPEA and 2,2-difluoroethanamine 4.112

VI.8 517 0.81 min (HPLC-B) P5 with 7 eq DIPEA and (2R)-2-aminopropanenitrile 4.113

VI.3 501 0.9 min (HPLC-M) P5 with 1.9 eq HATU, 7.9 eq DIPEA and (2R)-2-aminopropanenitrile 4.114

VI.3 490 0.39 min (HPLC-Q) P8 with propan-2- amine 4.115

VI.15 499 0.78 min (HPLC-B) P5 with 1.2 eq HATU, 2.2 eq DIPEA and 2-aminoacetonitrile 4.116

VI.4 522 0.71 min (HPLC-T) P5 with 2.5 eq HATU, 7 eq DIPEA and 3,3-difluoropropan-1- amine 4.117

VI.3 494 0.36 min (HPLC-Q) P8 with 2- fluoroethanamine 4.118

VI.18 532 0.82 min (HPLC-B) P5 with 2 eq DIPEA and (2S)-1,1,1-trifluoropropan-2- amine 4.119

VI.1 564 0.61 min (HPLC-V) P5 with 2,2,3,3,3- pentafluoropropan-1- amine4.120

VI.5 530 0.38 min (HPLC-Q) P8 with 1,3- difluoropropan-2- amine 4.121

VI.18 514 0.91 min (HPLC-M) P5 with 7.5 eq DIPEA and 1,3-difluoropropan-2- amine 4.122

VI.9 542 0.99 min (HPLC-M) P5 with 2 eq DIPEA and 2,2,2-trifluoroethanamine 4.123

VI.3 512 0.37 min (HPLC-Q) P8 with 2,2- difluoroethanamine 4.124

V1.9 543 0.63 min (HPLC-U) P9 with 2,2,2- trifluoroethanamine 4.125

VI.9 538 0.99 min (HPLC-M) P9 with 2,2- difluoroethanamine 4.126

VI.8 542 0.83 min (HPLC-B) P5 with 7 eq DIPEA and 1,1- difluoropropan-2-amine 4.127

VI.2 528 0.8 min (HPLC-I) 3.7 eq DIPEA and (S)-2,2,2-Trifluoro-1-methyl-ethylamine 4.128

VI.3 526 0.38 min (HPLC-Q) P8 with 1,3- difluoropropan-2- amine 4.129

VI.3 580 0.44 min (HPLC-Q) P8 with 2,2,3,3,3- pentafluoropropan-1- amine4.130

VI.3 526 0.39 min (HPLC-Q) P8 with 1,1- difluoropropan-2- amine 4.131

VI.4 522 0.38 min (HPLC-Q) P8 with 1,3- difluoropropan-2- amine 4.132

VI.4 497 0.37 min (HPLC-Q) P8 with 2- aminopropanenitrile 4.133

VI.18 500 0.36 min (HPLC-Q) P5 with 10 eq TEA and 2,2-Difluoro-ethylamine 4.134

VI.5 530 0.4 min (HPLC-Q) P8 with 1,1- difluoropropan-2- amine 4.135

VI.5 548 0.42 min (HPLC-Q) P8 with (2S)-1,1,1- trifluoropropan-2- amine4.136

VI.3 544 0.42 min (HPLC-Q) P8 with (2S)-1,1,1- trifluoropropan-2- amine4.137

VI.8 517 0.81 min (HPLC-B) P5 with 7 eq DIPEA and (2S)-2-aminopropanenitrile 4.138

VI.8 546 0.84 min (HPLC-B) P5 with 2 eq DIPEA and 2,2,2-trifluoroethanamine 4.139

VI.4 526 0.82 min (HPLC-B) P5 with 2,2,2- trifluoroethanamine 4.140

VII.14 514 0.73 min (HPLC-T) P9 with (2S)-2- aminopropanenitrile 4.141

VI.4 508 0.7 min (HPLC-T) P5 with 2,2- difluoroethanamine 4.142

VI.10 512 0.39 min (HPLC-Q) P5 with 2,2- difluoroethanamine 4.143

VI.13 576 1 min (HPLC-M) P9 with (2S)-1,1,1- trifluoropropan-2- amine4.144

VI.4 504 0.37 min (HPLC-Q) P8 with 3- fluoropropan-1-amine 4.145

VI.9 556 1.02 min (HPLC-M) P5 with (2R)-1,1,1- trifluoropropan-2- amine4.146

VI.13 558 0.98 min (HPLC-M) P9 with 1,1- difluoropropan-2- amine 4.147

VI.9 513 0.95 min (HPLC-M) P5 with 2 eq HATU, 7.8 eq DIPEA and (2S)-2-aminopropanenitrileGeneral Procedure 11 (P11) for Examples Shown in Table 5:

To a mixture of 1 eq of the corresponding amine, 2.5 eq DIPEA and DCMthe given amount of reagent is added slowly and the mixture is stirredat RT over night. The reaction mixture is washed with water, dried andconcentrated. If necessary the crude product is purified by HPLC or FC.

General Procedure 12 (P12) for Examples Shown in Table 5:

To a mixture of 1 eq of the corresponding amine, 5 eq DIPEA andacetonitrile the given amount of reagent is added slowly and the mixtureis stirred at RT for 2 h. Subsequently aqueous 2 mol/l K₂CO₃ solution isadded and the reaction mixture is passed through a short column of AloxB and concentrated. If necessary the crude product is purified by HPLCor FC.

The following examples in table 5 (example number given in column #) areprepared according to P11 or P12, details are given in the columnsynthesis comment, the retention-time and mass (ESI-MS m/z M+H⁺)determined by HPLC-MS are given in the columns MS and RT.

TABLE 5 # Structure SM MS RT Synthesis Comment 5.001

3.024 496 0.65 min (HPLC-B) P11 with 1.0 eq. methanesulfonyl chloride5.002

3.024 460 0.64 min (HPLC-B) P11 with 1.0 eq. acetyl chloride 5.003

3.018 496 0.65 min (HPLC-B) P11 with 1.0 eq. methanesulfonyl chloride5.004

3.024 514 0.71 min (HPLC-B) P11 with 1.0 eq. trifluoracetic acidanhydride 5.005

2.016 553 0.72 min (HPLC-B) P12 with 2.0 eq acetic acid and 1.1 eq HATU5.006

3.018 489 0.66 min (HPLC-B) P11 with 1.0 eq ethyl isocyanate 5.007

2.016 583 0.72 min (HPLC-B) P12 with 2.0 eq methoxyacetic acid and 1.1eq HATU 5.008

2.016 582 0.73 min (HPLC-B) P12 with 1.0 eq ethyl isocyanate 5.009

3.018 460 0.64 min (HPLC-B) P11 with 1.0 eq. acetyl chloride 5.010

3.018 514 0.71 min (HPLC-B) P11 with 1.0 eq. trifluoracetic acidanhydride 5.011

3.018 550 0.74 min (HPLC-B) P11 with 1.0 eq. trifluoro-methanesulfonylchloride 5.012

3.018 474 0.66 min (HPLC-B) P11 with 1.0 eq. propionyl chloride 5.013

2.016 569 0.74 min (HPLC-B) P12 with 1.0 eq methyl chloroformateGeneral Procedure 13 (P13) for Examples Shown in Table 6:

1 eq of the corresponding aryl fluoride 1.3 eq Cs₂CO₃ in a mixture ofthe respective alcohol and dioxane with the ratio 1:4 is stirred at 120°C. in a pressure vessel for the given time. If necessary, additionalCs₂CO₃ and alcohol are added and the reaction is continued at 120° C.for the given time. The reaction mixture is diluted with water andextracted with EtOAc. The organic layers are pooled dried andevaporated. If required, the crude product is further purified by FC orHPLC. Another example for the reaction and work-up is the synthesis ofVII.3.

To obtain the following examples (example number given in column #)shown in table 5, the corresponding compounds (example number given incolumn SM) are transformed according to P13. Details are given in thecolumn synthesis comment, the retention-time and mass (ESI-MS m/z M+H⁺)determined by HPLC-MS are given in the columns MS and RT.

TABLE 6 # Structure SM MS RT Synthesis Comment 6.001

4.136 556 0.87 min (HPLC-A) P13 100° C. with MeOH 6.002

4.123 524 0.69 min (HPLC-B) P13 90° C. with MeOH and Dioxane ascosolvent 6.003

4.1 556 0.86 min (HPLC-B) P13 90° C. with EtOH and Dioxane as cosolvent6.004

2.031 513 0.67 min (HPLC-B) P13 90° C. with MeOH and Dioxane ascosolvent

Example 7.005

0.2 g (0.56 mmol) Intermediate V.1, 0.2 g (1.67 mmol) K₂CO₃ and 0.1 g(0.83 mmol) 2-bromo-propionitrile and a catalytic amount of sodiumiodide in dimethylacetamide are stirred at RT for 2 days. The mixture isdiluted with brine and extracted with EtOAc. The organic layers aredried and evaporated. The residue is purified by FC.

Yield: 0.2 g (70%), ESI-MS: m/z=414 (M+H)+; R_(t)(HPLC): 0.65 min(HPLC-B)

Example 7.008

30.0 mg (0.08 mmol) Intermediate V.2, 70.0 mg (0.21 mmol) Cs₂CO₃ and0.01 mL (12.0 mmol) 2-bromo-propionitrile in 1 mL ACN are stirred 60° C.for 2 h. The mixture is diluted with water and extracted with DCM. Theorganic layer is separated, dried and evaporated. The residue ispurified by HPLC.

Yield: 15.4 mg (45%), ESI-MS: m/z=440 (M+H)⁺; R_(t)(HPLC): 0.50 min(HPLC-K)

Example 7.010 and Example 7.002

Separation of the enantiomeres obtained in example 15 (0.04 g; 0.08mmol), the absolute configuration is not determined. HPLC: Agilent 1260with Aurora A5 Fusion and DA-detector, Chiralcel OZ-H 4.6×250 mm, 5 μm(Daicel), 40° C., 150 bar backpressure, 75% scCO₂, 25% MeOH+0.2% DEA, 4ml/min

Isomer 1, Example 7.010: Yield: 0.01 g (41%), R_(t)(HPLC): 4.07 min

Isomer 2, Example 7.002: Yield: 0.01 g (39%), R_(t)(HPLC): 4.62 min

Example 7.006 and Example 7.007

Separation of the enantiomeres obtained in example 13 (0.03 g; 0.07mmol), the absolute configuration is not determined. HPLC: Agilent 1260with Aurora A5 Fusion and DA-detector, Chiralpak AS-H 4.6×250 mm, 5 μm(Daicel), 40° C., 150 bar backpressure, 85% scCO₂, 15% iPrOH+0.2% DEA, 4ml/min

Isomer 1, Example 7.006: Yield: 0.01 g (30%), R_(t)(HPLC): 3.94 min

Isomer 2, Example 7.007: Yield: 0.01 g (29%), R_(t)(HPLC): 4.49 min

Example 7.004 and Example 7.009

Separation of the enantiomeres obtained in example 175 (0.1 g; 0.31mmol), the absolute configuration is not determined. HPLC: Agilent 1260with Aurora A5 Fusion and DA-detector, Chiralcel OZ—H 4.6×250 mm, 5 μm(Daicel), 40° C., 150 bar backpressure, 70% scCO₂, 30% MeOH+0.2% DEA, 4ml/min

Isomer 1, Example 7.004: Yield: 0.04 g (31%), R_(t)(HPLC): 4.47 min

Isomer 2, Example 7.009: Yield: 0.03 g (22%), R_(t)(HPLC): 5.14 min

Example 7.003

50.0 mg (0.11 mmol) example 21, 40.0 mg (0.13 mmol) Cs₂CO₃ and 0.11 mL(26.0 mmol) methanol in 1 mL dioxane are stirred in a sealed flask at120° C. for 3 days. Additional Cs₂CO₃ and MeOH are added and the mixtureis stirred at 120° C. over night. The mixture is poured on ice water andextracted with DCM. The aqueous layer is extracted with EtOAc. Thecombined organic layers are dried and evaporated.

Yield: 17.0 mg (33%), ESI-MS: m/z=486 (M+H)⁺; R_(t) (HPLC): 1.12 min(HPLC-J)

Example 7.001

A mixture of 26.6 mg (0.043 mmol) example 34, 7 μl (0.086 mmol)formaldehyde, 3 μl (0.052 mmol) actic acid, 8 μlN,N-Diisopropylethylamine and 28 mg (0.128 mmol) NaBH₄ in 0.5 mL DMF arestirred at RT over night. The reaction mixture is purified by HPLC.

Yield: 12.0 mg (54%), ESI-MS: m/z=525 (M+H)⁺; R_(t) (HPLC): 0.85 min(HPLC-M)

Example 7.011

Step 1:

methyl(2R)-3-benzyloxy-2-[2-[(7-bromo-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoatewas prepared according to P3 from2-[(7-bromo-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenol(intermediate V.9 step 1) and (S)-3-Benzyloxy-2-hydroxy-propionic acidmethyl ester.

ESI-MS: m/z=540 (M+H)⁺; R_(t) (HPLC): 1.02 min (HPLC-E)

Step 2:

(2R)-3-benzyloxy-2-[2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenoxy]propanoicacid was prepared according to P2 (3 h 80° C.) from methyl(2R)-3-benzyloxy-2-[2-[(7-bromo-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoateand dimethyl sulfoximine (IV.1).

ESI-MS: m/z=539 (M+H)⁺; R_(t) (HPLC): 0.89 min (HPLC-E)

Step 3:

(2R)-3-benzyloxy-2-[2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenoxy]-N-(2,2,2-trifluoroethyl)propanamidewas prepared according to P5 from(2R)-3-benzyloxy-2-[2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenoxy]propanoicacid and 2,2,2-trifluoroethanamine.

ESI-MS: m/z=620 (M+H)⁺; R_(t) (HPLC): 0.95 min (HPLC-E)

Step 4:

A mixture of 50 mg (0.08 mmol)(2R)-3-benzyloxy-2-[2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenoxy]-N-(2,2,2-trifluoroethyl)propanamideand DCM was cooled to 5° C. and 0.1 ml (0.08 mmol) 1 mol/l solution ofBBr₃ in DCM was added dropwise. The reaction mixture was slowly warmedto RT and stirred over night. Aq. NaHCO₃ solution is added carefully andthe solvent evaporated. The crude product is purified via HPLC.

Yield: 27 mg (63%), ESI-MS: m/z=530 (M+H)⁺; R_(t) (HPLC): 0.81 min(HPLC-E)

Example 7.012

Is prepared in a similar manner as example 7.011 using ammonia insteadof 2,2,2-trifluoroethanamine.

ESI-MS: m/z=448 (M+H)⁺; R_(t) (HPLC): 0.70 min (HPLC-E)

Example 7.013

To a mixture of 25 mg (0.05 mmol) of example 7.011 and DCM 11 mg (0.07mmol) diethylaminosulfur trifluoride is added and the mixture is stirredover night. Aq. NaHCO₃ solution is added carefully and the mixture isextracted with DCM. The organic phases are pooled and evaporated. Thecrude product is purified via HPLC

Yield: 13 mg (50%), ESI-MS: m/z=532 (M+H)⁺; R_(t) (HPLC): 0.55 min(HPLC-V)

The invention claimed is:
 1. A compound of formula I:

wherein Ar is selected from a group consisting of:

wherein X is N; R³ is H, halogen, CN or C(═O)—NH₂; and R⁴ is selectedfrom a group consisting of:

wherein R⁷ is selected from a group consisting of H, CN, C₁₋₆-alkyl,—O—(C₁₋₃-alkyl), C₂₋₄-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,—(C₁₋₃-alkyl)-heterocyclyl, —(C₁₋₃-alkyl)-O-heterocyclyl, aryl,—(C₁₋₃-alkyl)-aryl, 5- or 6-membered heteroaryl,—(C₁₋₃-alkyl)-heteroaryl, —COOH, —(C═O)—O—(C₁₋₆-alkyl),—(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and —(C═O)—NR^(N1)R^(N2); wherein R^(N1) isH or C₁₋₃-alkyl; and R^(N2) is selected from a group consisting of H,C₁₋₆-alkyl, C₂₋₅-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,—(C₁₋₃-alkyl)-heterocyclyl, —(C₁₋₃-alkyl)-aryl and —SO₂—(C₁₋₃-alkyl); orR^(N1) and R^(N2) together with the N-atom to which they are attachedform a azetidinyl, pyrrolidinyl, piperidinyl, 4-oxo-piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl or 1-imino-1,4-thiazinane-1-oxide ring, whichmay be substituted with one OH, C₁₋₃-alkyl or —O—C₁₋₃-alkyl; and whereinin R⁴, each heterocyclyl is selected from a group consisting of 4-, 5-or 6-membered saturated monocyclic ring systems containing 1, 2 or 3heteroatoms independently of each other selected from the groupconsisting on O, S, N and NH, wherein one —CH₂— group may be replaced bya —C(═O)— group and wherein each heterocyclyl group is optionallysubstituted with C₁₋₃-alkyl; wherein in R⁴, each aryl is phenyl ornaphthyl; wherein in R⁴, each heteroaryl is selected from a groupconsisting of 5- or 6-membered monocyclic heteroaromatic ring systemscontaining 1, 2 or 3 heteroatoms independently of each other selectedfrom the group consisting of O, S, N and NH and is optionallysubstituted with C₁₋₃-alkyl; wherein in R⁴, each alkyl is optionallysubstituted with 1 or more F or with one or two substituentsindependently selected from the group consisting of CN, OH,—O—(C₁₋₃-alkyl), —O-tetrahydrofuranyl, NH₂, —NH—(C═O)—(C₁₋₃-alkyl),—NH—(C═O)—NH—(C₁₋₃-alkyl) or —NH—SO₂—(C₁₋₃-alkyl); and wherein in R⁴,each cycloalkyl is optionally substituted with 1 or more F or one CN,OH, CF₃, —O—(C₁₋₃-alkyl) or ═O; and R⁸ and R⁹ are independently of eachother selected from the group consisting of: H and C₁₋₃-alkyl optionallysubstituted with 1-3 F or one OH or NH₂; R¹ is selected from a groupconsisting of:

wherein R⁵ is selected from the group consisting of: a) C₁₋₃-alkyl,which is optionally substituted with a substituent selected from thegroup consisting of —O—(C₁₋₃-alkyl), —O—C₃₋₇-cycloalkyl,—O-heterocyclyl, C₃₋₇-cycloalkyl, heterocyclyl and phenyl, wherein eachalkyl group is optionally substituted with one or more F; and b)C₂₋₃-alkenyl, C₂₋₃-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl, heteroaryl,and aryl; wherein in R⁵ heteroaryl is a mono- or bicyclic ring systemcontaining 1, 2, 3 or 4 heteroatoms selected from N, O or S(O)_(r) withr=0, 1 or 2 wherein at least one of the heteroatoms is part of anaromatic ring, and wherein said ring system may have a carbonyl group,where each heterocyclyl is a saturated or unsaturated mono-, bi-, tri-or spirocarbocyclic ring system containing one or more heteroatomsselected from N, O or S(O)_(r) with r=0, 1 or 2, which in addition mayhave a carbonyl group and where aryl is a carbocyclic aromaticmonocyclic group containing 6 carbon atoms which may be further fused toa second 5- or 6-membered carbocyclic group which may be aromatic,saturated or unsaturated and R⁶ is C₁₋₃-alkyl which is optionallysubstituted with one or more F, or wherein R⁵ and R⁶ together with thesulfur atom to which they are attached form a 4 to 7-membered saturatedor partly unsaturated heterocycle that further to the sulfur atom maycontain one additional heteroatom selected from the group consisting ofO, S and NR^(N), wherein R^(N) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),—C(═O)—O—(C₁₋₄-alkyl), —C(═O)—(C₁₋₃-alkyl)-O—(C₁₋₄-alkyl), —C(═O)—NH₂,—C(═O)—NH(C₁₋₃-alkyl), —C(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl); andwherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶ together withthe sulfur atom to which they are attached may each be independentlysubstituted with halogen, CN, OH, NH₂, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂,—NH—C(═O)—(C₁₋₄-alkyl), —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—C(═O)—NH₂,—NH—C(═O)—NH—(C₁₋₄-alkyl), —NH—C(═O)—N(C₁₋₄-alkyl)₂,—N(C₁₋₄-alkyl)-C(═O)—(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)-C(═O)—O—(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)-C(═O)—NH₂, —N(C₁₋₄-alkyl)-C(═O)—NH—(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂, —O—(C₁₋₄-alkyl), C₁₋₆-alkyl,C₃₋₇-cycloalkyl, heterocylcyl, where heterocyclyl refers to a saturatedor unsaturated mono-, bi-, tri- or spirocarbocyclic ring systemcontaining one or more heteroatoms selected from N, O or S(O)_(r) withr=0, 1 or 2, which in addition may have a carbonyl group, heteroaryl,where heteroaryl refers to a mono- or bicyclic ring system containing 1,2, 3 or 4 heteroatoms selected from N, O or S(O)_(r) with r=0, 1 or 2wherein at least one of the heteroatoms is part of an aromatic ring, andwherein said ring system may have a carbonyl group, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄-alkyl), —C(═O)—N(C₁₋₄-alkyl)₂, —COOH,—C(═O)—O—(C₁₋₄-alkyl), —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl);—SO—(C₁₋₄-alkyl) or —SO₂—(C₁₋₄-alkyl); and R² is selected from a groupconsisting of halogen, CN, OH, NH₂, C₁₋₃-alkyl, C₂₋₃-alkenyl,C₂₋₃-alkynyl, C₃₋₅-cycloalkyl, —O-cyclopropyl and —S—C₁₋₃-alkyl, whereineach alkyl group is optionally substituted with one or more F; andwherein, if not otherwise specified, each alkyl group in the abovedefinitions is linear or branched and may be substituted with one tothree F; or a stereoisomer or salt thereof.
 2. The compound according toclaim 1, wherein R¹ is selected from a group consisting of:

wherein R⁵ is selected from the group consisting of: a) C₁₋₃-alkyl,which is optionally substituted with —O—(C₁₋₃-alkyl),—O—C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl, or phenyl, wherein each alkyl groupis optionally substituted with one or more F; and b) C₃₋₇-cycloalkyl,pyridinyl, and phenyl; and R⁶ is C₁₋₃-alkyl which is optionallysubstituted with one or more F; or wherein R⁵ and R⁶ together with thesulfur atom to which they are attached form a 4- to 7-membered saturatedor partly unsaturated heterocycle that further to the sulfur atom maycontain one additional heteroatom selected from the group consisting ofO, S and NR^(N), wherein R^(N) is H, C₁₋₃alkyl, —C(═O)—(C₁₋₃-alkyl),—C(═O)—O—(C₁₋₄-alkyl), —C(═O)—(C₁₋₃-alkyl)-O—(C₁₋₄-alkyl), —C(═O)—NH₂,—C(═O)—NH(C₁₋₃-alkyl), —C(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl); or asalt thereof.
 3. The compound according to claim 1, wherein R² isselected from a group consisting of F, Cl, Br, CH₃, CF₃, cyclopropyl and—O—CH₃, or a salt thereof.
 4. The compound according to claim 1, whereinAr is selected from a group consisting of:

or a salt thereof.
 5. The compound according to claim 1, wherein R⁴ isselected from a group consisting of:

wherein R⁷ is selected from a group consisting of CN, C₁₋₆-alkyl,—O—(C₁₋₃-alkyl), C₂₋₄-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,—(C₁₋₃-alkyl)-heterocyclyl, —(C₁₋₃-alkyl)-O-heterocyclyl, aryl,—(C₁₋₃-alkyl)-aryl, 5- or 6-membered heteroaryl,—(C₁₋₃-alkyl)-heteroaryl, —COOH, —(C═O)—O—(C₁₋₆-alkyl),—(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and —(C═O)—NR^(N1)R^(N2); wherein R^(N1) isH or C₁₋₃-alkyl; and R^(N2) is selected from a group consisting of H,C₁₋₆-alkyl, C₂₋₅-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,—(C₁₋₃-alkyl)-heterocyclyl, —(C₁₋₃-alkyl)-aryl, —SO₂—(C₁₋₃-alkyl); orR^(N1) and R^(N2) together with the N-atom to which they are attachedform a azetidinyl, pyrrolidinyl, piperidinyl, 4-oxo-piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl or 1-oxo-thiomorpholinyl ring,which may be substituted with one OH, C₁₋₃-alkyl or —O—C₁₋₃-alkyl; andwherein in the definition of R⁴, each heterocyclyl is selected from agroup consisting of 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl,2-oxo-oxazolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and[1,4]-dioxanyl and is optionally substituted with C₁₋₃-alkyl; wherein inthe definition of R⁴, each aryl is phenyl; wherein in the definition ofR⁴, each heteroaryl is selected from a group consisting of pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl,pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl and is optionallysubstituted with C₁₋₃-alkyl; wherein in the definition of R⁴, each alkylis optionally substituted with 1-3 F or with one or two substituentsindependently selected from the group consisting of CN, OH,—O—(C₁₋₃-alkyl), —O-tetrahydrofuranyl, NH₂, —NH—(C═O)—(C₁₋₃-alkyl),—NH—(C═O)—NH—(C₁₋₃-alkyl) or —NH—SO₂—(C₁₋₃-alkyl); and wherein in thedefinition of R⁴, each cycloalkyl is optionally substituted with 1-3 For one CN, OH, CF₃ or ═O; and R⁸ is selected from the group consistingof H and C₁₋₃-alkyl optionally substituted with 1-3 F or one OH or NH₂;or a salt thereof.
 6. The compound according to claim 1, wherein Ar isselected from a group consisting of:

wherein X is N; R³ is H, F, Cl, Br, CN or —C(═O)—NH₂; and R⁴ is selectedfrom a group consisting of:

wherein R⁷ is selected from a group consisting of CN, C₁₋₆ alkyl,C₃₋₇-cycloalkyl heterocyclyl, phenyl, 5- or 6-membered heteroaryl,—(C═O)—N═S(═O)(C₁₋₃-alkyl)₂ and —(C═O)—NR^(N1)R^(N2); wherein R^(N1) isH or C₁₋₃-alkyl; and R^(N2) is selected from a group consisting of H,C₁₋₆-alkyl, C₂₋₅-alkynyl, C₃₋₇-cycloalkyl, heterocyclyl,—(C₁₋₃-alkyl)-heterocyclyl, —(C₁₋₃-alkyl)-phenyl, —SO₂—(C₁₋₃-alkyl); orR^(N1) and R^(N2) together with the N-atom to which they are attachedform a azetidinyl, pyrrolidinyl, piperidinyl, 4-oxo-piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl or 1-oxo-thiomorpholinyl ring,which may be substituted with one OH, C₁₋₃-alkyl or —O—C₁₋₃-alkyl; andwherein in the definition of R⁴, each heterocyclyl is selected from agroup consisting of 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl,2-oxo-oxazolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and[1,4]-dioxanyl and is optionally substituted with C₁₋₃-alkyl; wherein inthe definition of R⁴, each heteroaryl is selected from a groupconsisting of pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl and is optionally substituted with C₁₋₃-alkyl; wherein inthe definition of R⁴, each alkyl is optionally substituted with 1-3 F orwith one or two substituents independently selected from the groupconsisting of CN, OH, —O—(C₁₋₃-alkyl), —O-tetrahydrofuranyl, NH₂,—NH—(C═O)—(C₁₋₃-alkyl), —NH—(C═O)—NH—(C₁₋₃-alkyl) or—NH—SO₂—(C₁₋₃-alkyl); and wherein in the definition of R⁴, eachcycloalkyl is optionally substituted with 1-3 F or one CN, OH, CF₃ or═O; and R⁸ is selected from a group consisting of H, CH₃, CH₂F, CF₃ andCH₂CH₃; R¹ is selected from a group consisting of:

wherein R⁵ is methyl or ethyl; and R⁶ is methyl or ethyl; or wherein R⁵and R⁶ together with the sulfur atom to which they are attached form a5- or 6-membered saturated heterocycle that in addition to the sulfuratom may contain one additional heteroatom selected from the groupconsisting of O and —NR^(N)—, wherein R^(N) is H, CH₃, —C(═O)—CH₃,—C(═O)—OCH₃, —C(═O)—CH₂—OCH₃ or —C(═O)—NH—CH₂CH₃; and R² is selectedfrom a group consisting of F, Cl, Br, CH₃, CF₃, cyclopropyl and —O—CH₃;and the pharmaceutically acceptable salts thereof.
 7. A pharmaceuticallyacceptable salt of a compound according to claim
 1. 8. A pharmaceuticalcomposition comprising a compound according to claim 1 or apharmaceutically acceptable salt thereof and optionally apharmaceutically acceptable carrier.
 9. The pharmaceutical compositionaccording to claim 8 further comprising an additional therapeutic agent.10. The pharmaceutical composition according to claim 9 wherein theadditional therapeutic agent is selected from an antidiabetic agent, alipid lowering agent, a cardiovascular agent, an antihypertensive agent,a diuretic agent, a thrombocyte aggregation inhibitor, an antineoplasticagent or an anti-obesity agent.